Total, methyl and inorganic mercury concentrations in blood and environmental exposure sources in newcomer women in Toronto, Canada.

Measurements of total blood Hg (tHg), often used as a proxy for methyl Hg (MeHg) concentrations, are most commonly the focus of population-based studies. Data on Hg species in biomarkers can allow for a more nuanced characterization of environmental exposure sources and risk but their availability is limited, especially for newcomer populations. The purpose of the Metals in Newcomer Women (MNW) study was to address existing data gaps on metal concentrations and exposure sources in newcomer women (19-45 years) and to examine tHg, MeHg and inorganic Hg (iHg) in the blood of East and South Asian women recently arrived to Toronto. Study participants were recruited in 2015 (n = 211). Total Hg concentrations were determined using both ICP-Q-MS and isotope dilution (ID)-SPME-GC-ICP-MS. A sample subset (n = 76) was chosen for the analysis of blood MeHg and iHg concentrations (also using ID-SPME-GC-ICP-MS). Hierarchical regression models were used to assess associations between blood tHg concentrations and environmental exposure factors for MNW participants. For the sample subset, a log-linear model was used to examine associations between blood iHg and MeHg concentrations and fish consumption patterns. The geometric mean (GM) blood tHg concentration was 1.05 µg/L (95% CI: 0.88-1.25), which was elevated compared to Canadian-born women (GM: 0.57 µg/L; 95% CI: 0.49-0.66), in a specialized data analysis of the Canadian Health Measures Survey (CHMS). GM concentrations for iHg and MeHg were 0.21 µg/L (95% CI: 0.16-0.28) and 2.66 µg/L (95% CI: 2.00-3.55), respectively. Significant distal determinants associated with blood tHg concentrations were: level of educational attainment, having lived in a coastal/fishing community prior to arrival, and global region of origin. Use of iron supplements and consumption of higher mercury fish species were also associated with tHg concentrations in the fully adjusted model. The study results demonstrate that blood Hg concentrations in newcomer women are slightly elevated, with some individuals in exceedance of recommended concentrations for women of reproductive age. The consumption of fish species low in Hg is recommended for newcomer women, especially those who consume fish frequently.

Blood cadmium concentrations and environmental exposure sources in newcomer South and East Asian women in the Greater Toronto Area, Canada.

BACKGROUND: Immigrant women are often identified as being particularly vulnerable to environmental exposures and health effects. The availability of biomonitoring data on newcomers is limited, thus, presenting a challenge to public health practitioners in the identification of priorities for intervention. OBJECTIVES: In fulfillment of data needs, the purpose of this study was to characterize blood concentrations of cadmium (Cd) among newcomer women of reproductive age (19-45 years of age) living in the Greater Toronto Area (GTA), Canada and to assess potential sources of environmental exposures. METHODS: A community-based model, engaging peer researchers from the communities of interest, was used for recruitment and follow-up purposes. Blood samples were taken from a total of 211 newcomer women from South and East Asia, representing primary, regional origins of immigrants to the GTA, and environmental exposure sources were assessed via telephone survey. Metal concentrations were measured in blood samples (diluted with 0.5% (v/v) ammonium hydroxide and 0.1% (v/v) octylphenol ethoxylate) using a quadrupole ICP-MS. Survey questions addressed a wide range of environmental exposure sources, including dietary and smoking patterns and use of nutritional supplements, herbal products and cosmetics. RESULTS: A geometric mean (GM) blood Cd concentration of 0.39µg/L (SD:±2.07µg/L) was determined for study participants (min/max: <0.045µg/L (LOD)/2.36µg/L). Several variables including low educational attainment (Relative Ratio (RR) (adjusted)=1.50; 95% CI 1.17-1.91), milk consumption (RR (adjusted)=0.86; 95% CI 0.76-0.97), and use of zinc supplements (RR (adjusted)=0.76; 95% CI 0.64-0.95) were observed to be significantly associated with blood Cd concentrations in the adjusted regression model. The variable domains socioeconomic status (R2adj=0.11) and country of origin (R2adj=0.236) were the strongest predictors of blood Cd. CONCLUSION: Blood Cd concentrations fell below those generally considered to be of human health concern. However, negative health effects cannot be entirely excluded, especially for those that fall in the upper percentile range of the distribution, given the mounting evidence for negative health outcomes at low environmental exposure concentrations.

Analysis of palladium concentrations in airborne particulate matter with reductive co-precipitation, He collision gas, and ID-ICP-Q-MS.

The concentration of platinum group elements (PGE) in the environment has increased significantly in the last 20 years mainly due to their use as catalysts in automotive catalytic converters. The quantitation of these metals in different environmental compartments is, however, challenging due to their very low concentrations and the presence of interfering matrix constituents when inductively coupled plasma-mass spectrometry (ICP-MS) is used for analysis. Previously, the research focus was on the analysis of platinum (Pt) and rhodium (Rh). However, due to the increasing use of palladium (Pd) in automotive catalytic converters, quantitation of this element in airborne particulate matter (PM) is also needed. Compared to Pt and Rh, measurements of Pd using ICP-MS are plagued by greater molecular interferences arising from elements such as copper (Cu), zinc (Zn) strontium (Sr), yttrium (Y), and zirconium (Zr). The aim of this study was to evaluate the applicability of reductive co-precipitation procedures using both mercury (Hg) and tellurium (Te) for the pre-concentration of Pd from airborne PM. Furthermore, helium (He) was tested as a collision gas for isotope dilution-inductively coupled plasma-quadrupole-mass spectrometry (ID-ICP-Q-MS) to measure Pd in the Hg and Te precipitates. Airborne PM samples (PM10) were collected from Neuglobsow (Brandenburg, north-eastern Germany) and Deuselbach (Rhineland-Palatinate, south-western Germany), considered to represent background levels, and from the city Frankfurt am Main (Hesse, Germany), a high-traffic area. Samples were first digested with aqua regia in a high-pressure asher (HPA) at 320 degrees C and 130 bar prior to the application of reductive co-precipitation procedures. The method was validated with road dust reference material BCR-723 and the CANMET-CCRMP reference material TDB-1 and WPR-1. In airborne PM collected at the background areas Neuglobsow and Deuselbach, Pd was detected with median concentrations values of 0.5 and 0.6 pg/m3, respectively. Much higher median concentration values of 14.8 pg Pd/m3 (detection limit = 0.01 pg Pd/m3) were detected in samples collected in the city of Frankfurt am Main. Results have shown that Hg co-precipitation depletes the concentrations of interfering matrix constituents by at least one order of magnitude more, compared to Te co-precipitation, making it a more effective method for the isolation and pre-enrichment of Pd from airborne PM prior to analysis. The use of a He gas flow of 120 ml/min in the plasma further minimized interferences, particularly those arising from CuAr+, YO+, and ZrO+ during the determination of Pd. The results demonstrate that Hg co-precipitation and the use of He collision gas, in combination with isotope dilution, are highly effective methods for the quantitation of Pd in airborne PM using ICP-MS.

Enhancement of fluorouracil uptake in human colorectal and gastric cancers by interferon or by high-dose methotrexate: An in vivo human study using noninvasive (19)F-magnetic resonance spectroscopy.

PURPOSE: To study whether two modulators, high-dose methotrexate (MTX) and interferon alfa-2a (IFNalpha-2a) will alter the intratumoral pharmacokinetics of fluorouracil (5-FU). PATIENTS AND METHODS: Five patients, two with gastric cancer and three with colorectal cancer, who had metastatic tumor nodules in their livers were studied dynamically in vivo after 5-FU injection. In a magnetic resonance imaging unit, noninvasive (19)F-magnetic resonance spectroscopy (MRS) was used to detect (19)F signals from 5-FU and its metabolites. RESULTS: The intratumoral half-life (t(1/2)) of 5-FU in these tumors ranged from 18.8 minutes to 42.3 minutes. Four of the five patients exhibited increases in the t(1/2) of 5-FU after intravenous (IV) administration of MTX or IFNalpha-2a. In the two patients with gastric cancer who received IV high-dose MTX followed by IV 5-FU, increases were seen in either the total t(1/2) of 5-FU (41.8%) or in the t(1/2) of the alpha phase (150%). In the three patients with colorectal cancer who received IV IFNalpha-2a followed by IV 5-FU, the two patients with partial responses had increases in the t(1/2) of 5-FU of 41% and 30.2%, whereas the nonresponder had a nonsignificant increase (5.6%) in the t(1/2) of 5-FU. CONCLUSIONS: These results document that the in vivo modulation of the tumoral pharmacokinetics of 5-FU can be measured noninvasively by (19)F-MRS and suggest that such information correlates with subsequent clinical outcomes. The findings also indicate that IFNalpha-2a and high-dose MTX can increase the intratumoral 5-FU in some patients. Such information, obtained prospectively in vivo, may assist in better individual cancer patient management and in developing novel drug combinations.

Inflammatory breast cancer: 10-year follow-up of a trial of surgery, chemotherapy, and allogeneic tumor cell/BCG immunotherapy.

A 10-year follow-up analysis has been performed on the cohort of 13 previously reported inflammatory breast cancer patients treated with chemotherapy, surgery, and allogeneic tumor cell/BCG vaccine. Follow-up of this duration is uncommon in the literature. Data indicate an apparent plateau of the survival curve at about 5 years, with 4 of 13 patients (31%) still alive after 10 years. Also noted is a long-term survival of an off-protocol patient with metastatic breast cancer treated with chemotherapy and vaccine. Although the role of vaccine cannot be directly determined from this study, this trial did demonstrate that long-term survival is a feasible goal for a significant fraction of patients with inflammatory breast cancer.

Interleukin-2 increases the antibody response in patients receiving autologous intralymphatic tumor cell vaccine immunotherapy.

The production of tumor-binding antibodies was studied in a group of cancer patients undergoing active specific immunotherapy with irradiated, cholesterol-treated, cell culture-derived autologous tumor cells injected by the intralymphatic route. Fifteen patients were analyzed: nine patients (four melanoma, one breast, one sarcoma, one colon, and one undifferentiated cancer) received three injections of 10 to 15 x 10(6) tumor cells, spaced 2 weeks apart, and six patients (two melanoma, two renal, one breast, and one colon cancer) received tumor cells admixed with 3 x 10(6) U recombinant interleukin-2 (IL-2) (Proleukin, Cetus, Emeryville, CA, USA) plus a 10-day intravenous infusion of 15 x 10(6) U/kg/day IL-2 after each immunization. Serum antibody binding to autologous tumor cells was measured at 2 and 4 weeks after initiation of therapy using an enzyme-linked immunosorbent assay with patient serum being added to adherent tumor cells bound to 96-well microtiter plates. After 4 weeks, we found a significant difference (0.02 less than P less than 0.04) in serum titer in the group receiving IL-2 (33% mean increase) compared with the non-IL-2 group (8% mean increase). Although neither group showed clinical improvement in response to the therapy, the results clearly demonstrated the efficacy of IL-2 in augmenting patient antibody response to autologous intralymphatic tumor cell immunization.

Clinical responses with active specific intralymphatic immunotherapy for cancer--a phase I-II trial.

We evaluated the method of active specific intralymphatic immunization to treat cancer in 32 patients with various tumor types as part of a broad-based phase I-II evaluation and describe the results of 3 sequential series. In series 1, the patients (n = 13) received 2 or more injections of autologous, cryopreserved, irradiated tumor cells directly into the lymphatic system through the cannulation of a dorsal pedal lymphatic channel. In series 2, the patients (n = 7) received low-dose cyclophosphamide, 300 mg per m2, 3 days before the autologous cell vaccine was administered. Series 3 (12 patients) was similar to series 2 except that the tumor cells were treated with cholesteryl hemisuccinate immediately before irradiation. Patients received from 2 to 6 injections of cells, depending on availability, at 2-week intervals. In all, 91 treatments are evaluated in this study. Clinical responses occurred in 7 of the 32 patients and were seen in all 3 series with about the same frequency. These responses occurred in cases of melanoma, lung cancer, colon cancer, and sarcoma. Regressions occurred in both visceral and subcutaneous sites. There was little toxicity, the chief side effect being local discomfort or inflammation. This experience indicates that active specific intralymphatic immunotherapy is safe, produces antitumor effects, and requires more investigation to increase the frequency and duration of observable tumor regression.

Phase II evaluation of vinblastine, methotrexate, and calcium leukovorin rescue in patients with refractory metastatic breast cancer.

Seventy-five evaluable patients with metastatic breast cancer refractory to frontline chemotherapy were treated with vinblastine 1.5 mg/m2 by continuous intravenous infusion for five days, intravenous infusion of methotrexate 200 mg/m2, and appropriate calcium leukovorin rescue. Thirty-eight patients were treated with vinblastine followed by methotrexate and calcium leukovorin, while 37 patients were treated with these same drugs in reverse sequence. In 17 patients (23%) an objective remission was achieved, while 39 remained stable for a period in excess of eight weeks. The median duration of remission was two months, and the median duration of survival was six months. The two regimens were well balanced for commonly used pretreatment prognostic factors. There was no difference in response rate and duration of response between the two treatment regimens. In patients with no prior exposure to methotrexate, the remission rate was 37% (11 of 30) compared with 13% (6 of 45). The treatment was well tolerated, and the dose-limiting toxicity was myelosuppression. This combination of drugs is effective in patients who have not been exposed to either drug, while it is only marginally effective in patients previously treated with methotrexate or vinblastine.

Phase II trial of bruceantin in metastatic breast carcinoma.

A phase II evaluation of bruceantin was carried out in 15 patients with refractory metastatic breast cancer. All patients had received extensive prior therapy including adriamycin, cytoxan, 5-FU, methotrexate, and a vinca alkaloid. Except for two patients with stable disease, no complete or partial response was observed. Drug toxicity, mainly nonhematologic, was severe, with nausea, vomiting, mild hypotension, and fever being the most frequently encountered.

Clinical pharmacology of bruceantin by radioimmunoassay.

During the phase I clinical trial of a new antitumor agent, bruceantin, the pharmacology was studied in 18 cancer patients. The drug was infused intravenously (IV) for 3 h at doses ranging from 1 to 3.6 mg/m2 per day for 5 days. The plasma drug disappearance curves were biphasic, with a fast initial half-life of less than 15 min. The second half-life (t1/2 beta) varied from 0.7 to 38 h among different patients and was not dose-related. The difference between the t1/2 beta on day 1 and that on day 5 was not significant. In patients with normal liver function, the mean plasma concentration at the end of infusion was 22 ng/ml, and the value of the area under the concentration X time curve (AUC) was 111 (ng/ml)h. In contrast, in patients with abnormal liver function the corresponding values were 115 ng/ml and 830 (ng/ml)h, respectively. In addition, these patients had a slower elimination half-life of 10.9 h and a decreased total clearance of 157 ml/min/m2, as compared with 2.6 h and 671 ml/min/m2, respectively, for the normal group. All these differences were statistically significant. Patients with abnormal liver function developed more severe toxicity, including fever, severe nausea, vomiting, and hypotension. Two patients with severe hepatic dysfunction received a reduced dose and developed no toxicity. These results demonstrated the importance of the effects of liver dysfunction on drug disposition and showed that the dosage should be reduced in patients with hepatic dysfunction.

Management of breast cancer patients failing adjuvant chemotherapy with adriamycin-containing regimens.

Sixty-two patients with breast cancer treated with Adriamycin-containing adjuvant chemotherapy developed recurrent disease. Four patients refused to take any form of systemic therapy at the time of relapse. Fifty-eight patients were managed with various treatment modalities, and of these 33 (57%) achieved on objective remission, 11 (19%) had stable disease and 14 patients (24%) did not respond to any form of therapy. Twenty-four patients received more than one treatment modality. Thirty-eight patients were treated with chemotherapy and 35 received endocrine therapy. Eight of 20 patients (40%) achieved objective remission upon retreatment with higher dose of 5-fluorouracil, Adriamycin, and cyclophosphamide at time of relapse, and seven of 18 patients (38%) treated with other chemotherapeutic agents showed objective remission. Fourteen of 35 patients (40%) achieved objective remission with hormonal therapies. The median survival from first relapse was 15 months for all patients, and was 25.7 months for responding patients. Survival was significantly longer in asymptomatic patients compared with those who were symptomatic from recurrent disease.

Chemoimmunotherapy for metastatic breast cancer with 5-fluorouracil, adriamycin, cyclophosphamide, methotrexate, L-asparaginase, Corynebacterium parvum, and Pseudomonas vaccine.

Moderate doses of methotrexate and L-asparaginase were added to standard doses fo 5-fluorouracil, Adriamycin, and cyclophosphamide in an attempt to improve the overall response rate and survival following chemotherapy. In addition, nonspecific immunotherapy with either Corynebacterium parvum or Pseudomonas vaccine was integrated into this prospective randomized clinical trial. The overall toxicity (degree of granulocytopenia and thrombocytopenia, length of myelosuppression, and incidence of myelosuppression-related infection and infectious deaths) increased considerably and led to the termination of patient accrual. The incidence of stomatitis and diarrhea was also increased with the addition of methotrexate and L-asparaginase, and apparently was potentiated by the addition of Pseudomonas vaccine to this five-drug combination.

Phase II study of hexamethylmelamine alone and in combination with mitomycin C and vincristine in advanced breast carcinoma.

Fifty-three patients with metastatic breast carcinoma were randomized to treatment with hexamethylmelamine (HMM) as a single agent versus a three-drug reimen of HMM, vincristine, and mitomycin C (HOM). All patients had received prior treatment with 5-fluorouracil, Adriamycin, and cyclophosphamide with or without methotrexate. HMM alone was used in a dose of 300 mg/m2/day x 14 days every 21 days. In the HOM regimen, the HMM dose was 200 mg/m2/day x 21 days, the vincristine dose was 1.5 mg on Days 1, 8, and 15, and the mitomycin C dose was 12 mg/m2 once every 6 weeks. No objective responses were observed with HMM in 15 evaluable patients. The HOM regimen resulted in five partial responses among the 27 evaluable patients. Gastrointestinal toxicity was the limiting toxicity of HMM, and thrombocytopenia was the major toxicity of the HOM regimen.

Combination chemotherapy with vincristine and methotrexate for advanced refractory breast cancer.

Eighteen patients with advanced breast cancer refractory to combination chemotherapy with 5-FU, Adriamycin, Cytoxan (FAC) were treated with methotrexate 30 to 40 mg/m2 iv and vincristing 1.5 mg/m2 iv at weekly intervals. Of 17 evaluable patients, 4 (23%) achieved a partial remission with a median duration of remission of 6 months and a median survival of 10 months. In another seven of seventeen patients (41%) the disease remained stable. Toxicity was minimal.

A human breast adenocarcinoma with chromosome and isoenzyme markers similar to those of the HeLa line.

Pleural effusion was obtained from a 51-year-old black woman who had breast adenocarcinoma and had received chemotherapy and radiation therapy after a radical mastectomy. Cytogenetic and isoenzymic analyses of the cells were performed within a few hours of obtaining the sample. Similar analyses were also done with a cell line established from this effusion. The stemline chromosome number was 35, one of the lowest in human neoplasms. In addition to a marker chromosome involving 1q, which is common in human breast tumors, we found several other marker chromosomes whose G-banding patterns were similar to some of the typical HeLa markers. Genetic signature analysis of 15 isoenzyme loci revealed that 13 were identical to those of HeLa. Both HeLa and the cell line described here express glucose-6-phosphate dehydrogenase type a, yet they were derived from heterozygotic individuals (ab). Our data indicate the necessity to extensive cytogenetic and biochemical analysis before conclusions are made that cell lines are actually intercell-line contaminants.

Electrocardiographic changes after adriamycin chemotherapy.

The electrocardiograms of 146 patients with metastatic carcinoma of the breast were reviewed before, during, and after the patients received Adriamycin (Doxorubicin) chemotherapy (AD). The most significant electrocardiographic change occurred in the amplitude of the QRS voltage. Seven patients developed cardiomyopathy after AD and showed a significant decrease in QRS voltage. This decrease, however, was more severe at the onset of congestive heart failure that at conclusion of Adriamycin. In 35 patients with pleural effusion, there was an inverse relation between the extent of the effusion and the amplitude of QRS voltage in the absence of congestive heart failure. These results indicate that 1) the sudden and relatively severe decrease in QRS voltage with the onset of CHF limits the value of this ECG criterion for predicting early Adriamycin toxicity, and 2) caution should be exercised in the interpretation of QRS voltage changes in patients with significant pleural effusion.