Association of Urine Platinum With Acute Kidney Injury in Children Treated With Cisplatin for Cancer.

Cisplatin is a chemotherapeutic agent highly excreted in urine and known to cause acute kidney injury (AKI). As AKI diagnosis by serum creatinine (SCr) is usually delayed, endeavors for finding early AKI biomarkers continue. This study aims to determine if urine platinum (UP) concentration 24 hours after cisplatin infusion is associated with AKI, and to evaluate the association between urine platinum and tubular damage biomarkers: neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1). Children treated with cisplatin in 12 Canadian centers (April 2013 to December 2017) were included. Urine from the morning after the first cisplatin infusion of the first or second cisplatin cycle was measured for urine platinum, NGAL, and KIM-1. SCr and serum electrolytes were used to detect AKI by either SCr elevation or urinary electrolyte wasting (potassium, magnesium, phosphate). The associations of urine platinum with AKI, NGAL, and KIM-1 were assessed. A total of 115 participants (54% boys, median age, 8.5 years; interquartile range, 4.0-13.4) were included, of which 29 (25%) and 105 (91%) developed AKI defined by SCr and electrolyte criteria, respectively. Higher urine platinum was associated with higher cisplatin dose (Spearman rho, 0.21) and with younger age (Spearman rho, -0.33). Urine platinum was not associated with postinfusion AKIor KIM-1, but was weakly associated with NGAL, particularly in participants without SCr AKI (Pearson's r, 0.22). Urine platinum may be a marker of mild tubular injury but is not likely to be a useful biomarker of clinically evident AKI.

Urinary excretion of platinum (Pt) following skin and respiratory exposure to soluble Pt at South African precious metals refineries.

Adverse respiratory and skin health effects have been associated with occupational exposure to soluble platinum (Pt). However, the relationship between skin exposure and urinary Pt excretion has not yet been investigated. In this study we examined the relationship between skin and respiratory exposure to soluble Pt and urinary Pt excretion at two South African precious metals refineries. The skin and respiratory exposure to soluble Pt as well as the urinary Pt excretion of forty precious metals refinery workers was assessed simultaneously using Ghostwipes™, Methods for the Determination of Hazardous Substances method 46/2 and spot urine tests, respectively. The geometric mean for skin exposure to soluble Pt on four anatomical positions (palm, wrist, neck and forehead) was 0.008 µg/cm2 [95% confidence interval (CI): 0.005-0.013 µg/cm2], while the geometric mean for respiratory exposure was 0.301 µg/m3 (95%CI: 0.151-0.601 µg/m3) and the geometric mean for urinary Pt excretion was 0.212 µg/g creatinine (95%CI: 0.169-0.265 µg/g creatinine). Partial correlations identified significant positive correlations between skin exposure, respiratory exposure and urinary Pt excretion (r = 0.580 to 0.754). Skin and respiratory exposures to soluble Pt were both positively correlated with urinary Pt excretion, and both exposure routes should be considered when investigating occupational exposure to soluble Pt.

Urinary excretion of platinum from South African precious metals refinery workers.

BACKGROUND: Urinary platinum (Pt) excretion is a reliable biomarker for occupational Pt exposure and has been previously reported for precious metals refinery workers in Europe but not for South Africa, the world's largest producer of Pt. OBJECTIVE: This study aimed to quantify the urinary Pt excretion of South African precious metals refinery workers. METHODS: Spot urine samples were collected from 40 workers (directly and indirectly exposed to Pt) at two South African precious metals refineries on three consecutive mornings prior to their shifts. Urine samples were analysed for Pt using inductively coupled plasma-mass spectrometry and were corrected for creatinine content. RESULTS: The urinary Pt excretion of workers did not differ significantly between sampling days. Urinary Pt excretions ranged from <0.1 to 3.0 µg Pt/g creatinine with a geometric mean of 0.21 µg Pt/g creatinine (95% CI 0.17 to 0.26 µg Pt/g creatinine). The work area (P=0.0006; η2=0.567) and the number of years workers were employed at the refineries (P=0.003; η2=0.261) influenced their urinary Pt excretion according to effect size analyses. Directly exposed workers had significantly higher urinary Pt excretion compared with indirectly exposed workers (P=0.007). CONCLUSION: The urinary Pt excretion of South African precious metals refinery workers reported in this study is comparable with that of seven other studies conducted in precious metals refineries and automotive catalyst plants in Europe. The Pt body burden of workers is predominantly determined by their work area, years of employment in the refineries and whether they are directly or indirectly exposed to Pt.

Antineoplastic drug residues inside homes of chemotherapy patients.

Chemotherapy treatment of cancer patients has shifted from inpatient to outpatient administration. Thus, family members are potentially exposed to cytotoxic drug residues from patients' excretions inside their homes. The study's aim was to evaluate the surface contamination and the potential uptake of antineoplastic drug residues by family members at home of chemotherapy patients. Overall, 265 wipe samples from 13 homes were taken at two times after chemotherapy from different surfaces (toilet, bathroom, kitchen). 62 urine samples were collected from patients and family members on three days. Samples were analyzed for cyclophosphamide, 5-fluorouracil (urine: FBAL) and platinum (as marker for cis-, carbo- and oxaliplatin). Substantial contamination was found on every surface type (PT: 0.02-42.5pg/cm2, 5-FU: ND-98.3pg/cm2, CP: ND-283.3pg/cm2) with highest concentrations on toilet and bathroom surfaces. While patients' urinary drug concentrations often were elevated for more than 48h after administration, no drug residues were detectable in the family members' urine. This study provided an insight in the exposure situation against antineoplastic drug residues at home of chemotherapy patients. As contamination could be found on various surfaces adequate hygienic and protective measures are necessary to minimize the exposure risk for cohabitants.

Exposure of the German general population to platinum and rhodium - Urinary levels and determining factors.

In this study the exposure of the general population in Germany to platinum and rhodium and its determinants was investigated in 259 participants (subdivided in three groups) by urine analyses and assessment of the dental status. Complementary, an interview including questions characterising possible exposure to traffic exhaust was conducted. The median excretion was 2.42ng platinum/g creatinine and 7.27ng rhodium/g creatinine. The detailed analysis of the collected data showed significant higher platinum excretion values with increasing number of surfaces covered with restorations containing precious metals (R=0.389; p<0.001), but also higher values for habitants of urban areas (median=3.43ng/g creatinine; 95th percentile=25.2ng/g) compared with those of rural areas (median=2.06ng/g creatinine; 95th percentile=20.0ng/g). Also, participants working in urban areas showed higher platinum excretion values (median=3.27ng/g; 95th percentile=19.6ng/g). Male participants living and working next to highly frequented roads showed higher rhodium excretion values (median=7.27ng/g; 95th percentile=13.5 ng/g). In summary, the study showed that exhaust emissions have an influence on platinum and rhodium excretion, but for platinum this influence is rather low compared to the influence of precious metals containing restorations.

A label-free colorimetric aptasensor for simple, sensitive and selective detection of Pt (II) based on platinum (II)-oligonucleotide coordination induced gold nanoparticles aggregation.

Herein, a gold nanoparticles (AuNPs) based label-free colorimetric aptasensor for simple, sensitive and selective detection of Pt (II) was constructed for the first time. Four bases (G-G mismatch) mismatched streptavidin aptamer (MSAA) was used to protect AuNPs from salt-induced aggregation and recognize Pt (II) specifically. Only in the presence of Pt (II), coordination occurs between G-G bases and Pt (II), leading to the activation of streptavidin aptamer. Streptavidin coated magnetic beads (MBs) were used as separation agent to separate Pt (II)-coordinated MSAA. The residual less amount of MSAA could not efficiently protect AuNPs anymore and aggregation of AuNPs will produce a colorimetric product. With the addition of Pt (II), a pale purple-to-blue color variation could be observed by the naked eye. A detection limit of 150nM and a linear range from 0.6µM to 12.5µM for Pt (II) could be achieved without any amplification.

Inductively coupled plasma mass-spectrometric determination of platinum in excretion products of client-owned pet dogs.

Residues of antineoplastic drugs in canine excretion products may represent exposure risks to veterinary personnel, owners of pet dogs and other animal care-takers. The aim of this study was to measure the extent and duration of platinum (Pt) excretion in pet dogs treated with carboplatin. Samples were collected before and up to 21 days after administration of carboplatin. We used validated, ultra-sensitive, inductively coupled plasma-mass spectrometry assays to measure Pt in canine urine, faeces, saliva, sebum and cerumen. Results showed that urine is the major route of elimination of Pt in dogs. In addition, excretion occurs via faeces and saliva, with the highest amounts eliminated during the first 5 days. The amount of excreted Pt decreased over time but was still quantifiable at 21 days after administration of carboplatin. In conclusion, increased Pt levels were found in all measured excretion products up to 21 days after administration of carboplatin to pet dogs, with urine as the main route of excretion. These findings may be used to further adapt current veterinary guidelines on safe handling of antineoplastic drugs and treated animals.

Silicone implants--a possible confounder for urinary platinum background concentrations?

INTRODUCTION: Urinary platinum excretion from occupationally unexposed population is very low. Up to now, in Germany, dental noble metal alloys and a platinum based chemotherapy have been identified as reason for elevated urine concentrations. As fabrication of silicone involves platinum as catalyst, this study examines the potential release of platinum from silicone breast implants by quantifying urinary platinum concentration. METHODS AND RESULTS: Platinum release from three different types of silicone implants into saline solution was measured in a laboratory experiment. It showed a strong increase of platinum concentration during the first 30 min and high platinum concentrations even after 60 h. In the following field study urinary platinum concentrations were determined from 30 women with dental gold alloy restorations and 28 women without such dental inlays. Median platinum concentrations were 5.2 ng/l urine (21.2 ng/g creatinine) for the women with dental gold inlays and 6.0 ng/l urine (5.4 ng/g creatinine) for those without. Compared with the urinary platinum concentrations provided by the German Environmental Survey (GerES) for the general female population the urinary platinum levels of women with silicone implants of the presented study were significantly higher, both for the study groups with and without dental gold alloy inlays. CONCLUSIONS: Silicone breast implants must be considered as a new confounder and as a further contributor to elevated urinary platinum concentrations in human platinum background reference values of women.

Investigation on pharmacokinetics, tissue distribution and excretion of a novel platinum anticancer agent in rats by inductively coupled plasma mass spectrometry (ICP-MS).

1. DN604 is a new platinum agent with encouraging anticancer activity. The present study was to explore the pharmacokinetic profiles, distribution and excretion of platinum in Sprague-Dawley rats after intravenous administration of DN604. A sensitive and selective inductively coupled plasma mass spectrometry (ICP-MS) method was established for determination of platinum in biological specimens. The pharmacokinetic parameters were calculated by a non-compartmental method. 2. The area under concentration-time curve AUC0-t and AUC0-∞ for platinum originating from DN604 at 10 mg/kg were 25.15 ± 1.29 and 28.72 ± 1.04 µg/hml, respectively. The mean residence time MRT was 36.59 ± 6.65 h. The volume of distribution Vz was 11.42 ± 2.49 l/kg and clearance CL was 0.18 ± 0.01 l/h/kg. In addition, the elimination half-life T1/2z was 44.83 ± 9.75 h. After intravenous administration of DN604, platinum was extensively distributed in most of tested tissues except brain. The majority of platinum excreted via urine, and its accumulative excretion ratio during the period of 120 h was 63.5% ± 7.7% for urine, but only 6.94% ± 0.11% for feces. 3. The satisfactory half-life, wide distribution and high excretion made this novel platinum agent worthy of further research and development.

Flow injection analysis with electrochemical detection for rapid identification of platinum-based cytostatics and platinum chlorides in water.

Platinum-based cytostatics, such as cisplatin, carboplatin or oxaliplatin are widely used agents in the treatment of various types of tumors. Large amounts of these drugs are excreted through the urine of patients into wastewaters in unmetabolised forms. This phenomenon leads to increased amounts of platinum ions in the water environment. The impacts of these pollutants on the water ecosystem are not sufficiently investigated as well as their content in water sources. In order to facilitate the detection of various types of platinum, we have developed a new, rapid, screening flow injection analysis method with electrochemical detection (FIA-ED). Our method, based on monitoring of the changes in electrochemical behavior of analytes, maintained by various pH buffers (Britton-Robinson and phosphate buffer) and potential changes (1,000, 1,100 and 1,200 mV) offers rapid and cheap selective determination of platinum-based cytostatics and platinum chlorides, which can also be present as contaminants in water environments.

Speciation of platinum in blood plasma and urine by micelle-mediated extraction and graphite furnace atomic absorption spectrometry.

A highly sensitive and selective technique for the speciation of platinum by cloud point extraction prior to determination by graphite furnace atomic absorption spectrometry (GFAAS) was described. The separation of Pt(II) from Pt(IV) was performed in the presence of 4-(p-chlorophenyl)-1-(pyridin-2-yl)thiosemicarbazide (HCPTS) as chelating agent and Triton X-114 as a non-ionic surfactant. The extraction of Pt(II)-HCPTS complex needs temperature higher than the cloud point temperature of Triton X-114 and pH = 7, while Pt(IV) remains in the aqueous phase. The Pt(II) in the surfactant phase was analyzed by GFAAS, and the concentration of Pt(IV) was calculated by subtraction of Pt(II) from total platinum which was directly determined by GFAAS. The effect of pH, concentration of chelating agent, surfactant, and equilibration temperature were investigated. An enrichment factor of 42 was obtained for the preconcentration of Pt(II) with 50 mL solution. Under the optimum experimental conditions, the calibration curve was linear up to 30 µgL(-1) with detection limit of 0.08 µgL(-1) and the relative standard deviation was 1.8%. No considerable interference was observed due to the presence of coexisting anions and cations. The accuracy of the results was verified by analyzing different spiked samples (tap water, blood plasma and urine). The proposed method was applied to the speciation analysis of Pt in blood plasma and urine with satisfactory results.

Environmental and biological monitoring of platinum-containing drugs in two hospital pharmacies using positive air pressure isolators.

Environmental and biological monitoring of platinum containing drugs was implemented in two French hospital pharmacies using positive air pressure isolators and having similar working procedures when preparing antineoplastic drugs. Wipe sampling of surfaces, gloves, and vials was performed in the preparation room and in storage areas. All employees involved in the preparation of antineoplastic drugs were tested for urinary platinum on Monday before work and Friday after shift. Only traces of platinum were detected on surfaces in the preparation room outside the isolators (less than 1.61 pg cm(-2)). However, in one center, significant contamination was found in the storage area of the drug vials, which can most likely be linked to the rupture of a platinum vial and due to inefficient cleaning procedures. Surfaces inside the isolators were found to be contaminated (maximum: 198.4 pg cm(-2)). A higher level of contamination was detected in one pharmacy and could be explained by the lack of overgloving with regular changes during the preparation process. Nitrile gloves used during drug handling outside the isolator showed the highest platinum concentration (maximum: 5.86 ng per pair). With regards to platinum urine concentration, no significant difference was found between exposed and unexposed pharmacy personnel. Isolator technology combined with individual protective measures seems to be efficient to protect workers from occupational exposure to antineoplastic drugs, whereas specific individual protective procedures implemented were focussing on the risk of handling vials outside the isolator (e.g. high frequency of glove changing). Moreover, overgloving inside the isolator would contribute to substantially decrease inner surface contamination and should be recommended in order to limit the transfer of chemical contamination to the end products.

Urinary excretion of platinum, arsenic and selenium of cancer patients from the Antofagasta region in Chile treated with platinum-based drugs.

BACKGROUND: Arsenic exposure increases the risk of non-cancerous and cancerous diseases. In the Antofagasta region in Chile, an established relationship exists between arsenic exposure and the risk of cancer of the bladder, lung and skin. Platinum-based drugs are first-line treatments, and many works recognise selenium as a cancer-fighting nutrient. We characterised the short-term urinary excretion amounts of arsenic, selenium and platinum in 24-h urine samples from patients with lung cancer and those with cancer other than lung treated with cisplatin or/and carboplatin. As - Se - Pt inter-element relationships were also investigated. RESULTS: The amounts of platinum excreted in urine were not significantly different between patients with lung cancer and those with other cancers treated with cisplatin, despite the significant variation in platinum amounts supplied from platinum-based drugs. In general, the analytical amounts of excreted selenium were greater than those for arsenic, which could imply that platinum favours the excretion of selenium. For other types of cancers treated with drugs without platinum, excretion of selenium was also greater than that of arsenic, suggesting an antagonist selenium-anti-cancer drug relationship. CONCLUSIONS: Regards the baseline status of patients, the analytical amounts of excreted Se is greater than those for As, particularly, for cisplatin chemotherapy. This finding could imply that for over the As displacement Pt favours the excretion of Se. The analytical amounts of excreted Se were greater than those for As, either with and without Pt-containing drugs, suggesting an antagonist Se-anti-cancer drug relationship. However, it seemed that differences existed between As - Se - Pt inter-element associations in patients treated for lung cancer in comparison with those treated for cancer other than lung. Therefore, knowledge obtained in this work, can contribute to understanding the arsenic cancer mechanism and the As - Se - Pt inter-element association for lung cancer and other types of cancer, which in some cases respond at a linear mathematical model.

Novel potassium N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhex-1-yl]-L-amino acid dichloroplatinates(II) with high anti-tumor activity and low side reaction.

To discover whether novel anti-tumor platinum agents are capable of selectively accumulating in tumor tissue, three novel potassium N-[(2S,3R,4R,5R)-2,3,4,5,6-pentahydroxylhex-1-yl]-L-amino acid dichloroplatinates(II) were prepared. At a dose of 1.67 µmol kg(-1) the in vivo anti-tumor potencies of two of the compounds were higher than that of oxaliplatin. The mortality analysis indicated that these compounds resulted in a 100% survival rate, whereas oxaliplatin lead to an 80% survival rate. The organ damage examination indicated that these compounds induced less damage than oxaliplatin. The platinum accumulation in the organs, blood and bone was significantly lower than that of oxaliplatin treated mice, while the platinum accumulation in the tumor tissue was significantly higher than that of the oxaliplatin treated mice.

Determination of platinum originating from carboplatin in human urine and canine excretion products by inductively coupled plasma mass spectrometry.

We present highly sensitive, rapid methods for the determination of Pt originating from carboplatin in human urine and canine urine, feces, and oral fluid. The methods are based on the quantification of Pt by inductively coupled plasma mass spectrometry, and allow quantification of 7.50 ng/L Pt in human and canine urine (in 15 µL of matrix), 15.0 ng/L Pt in canine oral fluid (in 15 µL of matrix), and 0.105 ng/g Pt in canine feces (in 5 µg of matrix). Sample pretreatment mainly involved dilution with appropriate diluents. The performance of the methods fulfilled the most recent FDA guidelines for bioanalytical method validation. Validated ranges of quantification were 7.50 to 1.00 × 10(4) ng/L Pt in human and canine urine, 0.105-30.0 ng/g Pt in canine feces, and 15.0 to 1.00 × 10(4) ng/L Pt in canine oral fluid. Canine urine and oral fluid cannot be easily obtained. Therefore, we also investigated the validity of the usage of human matrix samples for the preparation of calibration standards and quality control samples as alternatives, to be used in future clinical studies. The assays are used to support biomonitoring studies and pharmacokinetic studies in pet dogs treated with carboplatin.

Evaluation of environmental contamination by platinum and exposure risks for healthcare workers during a heated intraperitoneal perioperative chemotherapy (HIPEC) procedure.

UNLABELLED: The study was plan to assess platinum (Pt) contamination in the operating room and its exposure to health workers during heated intraperitoneal perioperative chemotherapy (HIPEC) using oxaliplatin. MATERIALS AND METHODS: Pt was measured in urinary and environmental (air and surfaces) samples via inductively coupled plasma mass spectrometry (ICP-MS). Urinary samples were obtained from 11 members of the staff before and after the procedure and from 6 controls. Samples from 15 surfaces and from 3 filters from the air extractors were also analyzed for Pt contamination. RESULTS: Before HIPEC, Pt levels in urinary samples were similar in both the exposed and control groups; concentrations were below the limit of detection (i.e., 1.5 ng/L). No elevation was observed in the exposed group at the end of the procedure. Surgeon gloves were heavily contaminated. On other analyzed surfaces, lesser amounts of Pt were measured, ranging from 2 ng on the surgeon's hands to 183 ng on the forceps. All three air filters tested negative. CONCLUSION: No contamination of healthcare workers or of the air in the operating room was detected. However, the heavy contamination of the surgeon's gloves demonstrates why doubling of specialized gloves for the surgeon should be mandatory.

Determination of Rh, Pd and Pt in urine samples using a pre-concentration sequential injection analysis system coupled to a quadrupole-inductively coupled plasma-mass spectrometer.

The proposed flow system was developed in order to minimize the drawbacks related to the PGEs determination by quadrupole-inductively coupled plasma-mass spectrometry (Q-ICP-MS). It was intended not only to lower the limits of detection (LODs) but also to eliminate the interferences originating from some atomic and molecular ions produced in the argon plasma. This was accomplished by means of an on-line sample clean-up/pre-concentration step, using a chelating resin (Metalfixtrade mark Chelaminetrade mark) in which Rh, Pd and Pt were preferably retained when compared with the interfering species. The results obtained by using the developed flow system in the analysis of urine samples are presented. With a sampling rate of 9 samples h(-1) (i.e., 27 determinations) and a sample consumption of ca. 10 mL, the developed flow system allowed linear calibration plots up to 100 ngL(-1) with detection limits of 1.2 ngL(-1) (Rh), 0.4 ngL(-1) (Pd) and 0.9 ngL(-1) (Pt). Repeatability studies showed good precision (R.S.D.%, n=5): 3.7% (Rh); 2.6% (Pd) and 2.4% (Pt), for 10 ngL(-1); 2.4% (Rh); 1.4% (Pd) and 1.9% (Pt), for 50 ngL(-1); and 1.3% (Rh); 0.58% (Pd) and 0.62% (Pt), for 100 ngL(-1). By spiking human urine samples, recovery tests were performed, and the values obtained ranged between 89% and 105% (Rh); 90% and 104% (Pd); and 93% and 105% (Pt).

Biomonitoring of tram drivers exposed to airborne platinum, rhodium and palladium.

OBJECT: The aim of this study was to evaluate urinary levels of Pt, Rh and Pd in occupationally exposed subjects. METHODS: A total of 122 healthy male subjects of Rome (Italy) were studied; 64 were municipal tram drivers and 58 control subjects. Metal quantification in the urine samples was carried out by sector field inductively coupled plasma mass spectrometry. RESULTS: There were statistically significant differences between urinary Pt and Rh levels of the workers and the control group (Pt median: 1.23 versus 1.03 ng/g creatinine; Rh median: 19.16 versus 11.18 ng/g creatinine), while no difference in Pd levels was observed (Pd median: 11.47 versus 8.75 ng/g creatinine). CONCLUSIONS: Urinary Pt and Rh could be useful biomarkers for monitoring population groups occupationally exposed to these elements. Urinary concentration of Pt and Rh, though still low, could be of some concern in workers heavily exposed to urban car traffic.

Comments on total platinum concentration and platinum oxidation states in body fluids, tissue, and explants from women exposed to silicone and saline breast implants by IC-ICPMS.

The paper by Lykissa and Maharaj (Lykissa, E. D.; Maharaj, S. V. M Anal. Chem. 2006, 78, 2925-2933) purports to provide evidence that the urine of women with silicone breast implants contain 60 to over 1700 times more platinum in their urine that the urine of people with no known exposure to platinum. Further, they purport to show evidence that the platinum used in the manufacture of breast implants (Pt0) is converted by a unknown process to yield highly oxidized platinum species, stable in biological matrixes, up to and including Pt6+. This correspondence poses three questions associated with the work and directs the reader's attention to the data, which clearly show that the blood and urine platinum levels in implanted women and their healthy control group were not significantly different from one another.