Acute pesticide illnesses associated with off-target pesticide drift from agricultural applications: 11 States, 1998-2006

Background: Pesticides are widely used in agriculture, and off-target pesticide drift exposes workers and the public to harmful chemicals.Objective: We estimated the incidence of acute illnesses from pesticide drift from outdoor agricultural applications and characterized drift exposure and illnesses.Methods: Data were obtained from the National Institute for Occupational Safety and Health’s Sentinel Event Notification System for Occupational Risks–Pesticides program and the California Department of Pesticide Regulation. Drift included off-target movement of pesticide spray, volatiles, and contaminated dust. Acute illness cases were characterized by demographics, pesticide and application variables, health effects, and contributing factors.Results: From 1998 through 2006, we identified 2,945 cases associated with agricultural pesticide drift from 11 states. Our findings indicate that 47% were exposed at work, 92% experienced low-severity illness, and 14% were children (< 15 years). The annual incidence ranged from 1.39 to 5.32 per million persons over the 9-year period. The overall incidence (in million person-years) was 114.3 for agricultural workers, 0.79 for other workers, 1.56 for nonoccupational cases, and 42.2 for residents in five agriculture-intensive counties in California. Soil applications with fumigants were responsible for the largest percentage (45%) of cases. Aerial applications accounted for 24% of cases. Common factors contributing to drift cases included weather conditions, improper seal of the fumigation site, and applicator carelessness near nontarget areas.Conclusions: Agricultural workers and residents in agricultural regions had the highest rate of pesticide poisoning from drift exposure, and soil fumigations were a major hazard, causing large drift incidents. Our findings highlight areas where interventions to reduce off-target drift could be focused.     

Acute pesticide poisoning in the U.S. retail industry, 1998-2004

OBJECTIVE: This study was conducted to describe the national magnitude and characteristics of acute pesticide poisoning among workers and customers in retail establishments. METHODS: Analyses included retail employees 15-64 years of age and customers with acute pesticide poisoning identified from the Sentinel Event Notification System for Occupational Risks-Pesticides (SENSOR-Pesticides) and California Department of Pesticide Regulation from 1998 to 2004. Pesticide poisoning incidence rates and incidence rate ratios (IRR) were calculated. RESULTS: A total of 325 cases of acute pesticide poisoning were identified. Of these cases, 287 (88%) were retail employees and 38 (12%) were customers. Overall, retail employees had a significantly lower acute pesticide poisoning incidence rate compared with non-agricultural, non-retail employees (IRR=0.53; 95% confidence interval 0.47, 0.59). However, significantly elevated pesticide poisoning incidence rates were observed for four retail occupations (janitors, stock handlers/baggers, bakery/deli clerks, and shipping/receiving handlers). In addition, workers employed in two retail industry sectors (farm supply stores and hardware stores) had significantly elevated acute pesticide poisoning incidence rates. Incidence rates among the retail employees demonstrated a quadratic trend, monotonically decreasing from 1998 to 2000 and monotonically increasing from 2000 to 2003. The rates appear to have leveled off in 2003 and 2004. CONCLUSIONS: Preventive measures to decrease acute pesticide poisoning incidence in the retail sector include adoption of unbreakable and tear-resistant container requirements, increased utilization of integrated pest management strategies, and advisement to store managers, employees, and customers about poisoning prevention.     

The use of whole exome sequencing and murine patient derived xenografts as a method of chemosensitivity testing in sarcoma

Background

Soft tissue and bone sarcoma represent a broad spectrum of different pathology and genetic variance. Current chemotherapy regimens are derived from randomised trials and represent empirical treatment. Chemosensitivity testing and whole exome sequencing (WES) may offer personalized chemotherapy treatment based on genetic mutations.

Methods

A pilot, prospective, non-randomised control experimental study was conducted. Twelve patients with metastatic bone or soft tissue sarcoma that had failed first line chemotherapy treatment were enrolled for this study. Human tissue taken at surgical biopsy under general anaesthetic was divided between two arms of the trial. Subsections of the tumour were used for WES and the remainder was implanted subcutaneously in immunodeficient mice (PDX). Results of WES were analysed using a bioinformatics pipeline to identify mutations conferring susceptibility to kinase inhibitors and common chemotherapeutic agents. PDX models exhibiting successful growth underwent WES of the tumour and subsequent chemosensitivity testing.

Results

WES was successful in all 12 patients, with successful establishment PDX tumours models in seven patients. WES identified potential actionable therapeutics in all patients. Significant variation in predicted therapeutics was demonstrated between three PDX samples and their matched tumour samples.

Conclusion

Analysis of WES of fresh tumour specimens via a bioinformatics pipeline may identify potential actionable chemotherapy agents. Further research into this field may lead to the development of personalized cancer therapy for sarcoma.

     

Increased "pregnancy-specific" beta1-glycoprotein in certain nonseminomatous germ cell tumors.

Schwangerschafts (pregnancy) protein No. 1 (SP1), a recently identified beta1-glycoprotein that occurs during pregnancy, was assayed in the sera of 97 men with germ cell tumors of the testis. SP1 was elevated at 11-440 ng/ml in 3 of 6 men with choriocarcinomas, in 5 of 17 men with teratomas or "teratocarcinomas" (embryonal carcinomas and teratomas), and in 5 of 50 men with embryonal carcinomas; the highest value in 143 patients with nonmalignant diseases was 9.1 ng/ml. None of 24 sera from men with seminomas and none of 5 sera from men with orchitis had elevated SP1. In the 1 patient examined, testicular choriocarcinoma SP1 had immunochemical and gel chromatographic properties similar to those of highly purified SP1 of placental origin.     

Treatment with lovastatin,cholestyramine or niacin alters K-ras membrane association in mouse lung in a strain-dependent manner: results in females

Hypocholesterolemic drugs may themselves increase (cholestyramine, CS) or decrease (lovastatin, Lov) peripheral tissue de novo cholesterol biosynthesis. This will alter the abundance of prenyl groups and potentially increase (CS) or decrease (Lov) K-ras membrane localization, with possible pro- or anti-carcinogenic effects (K-ras is a proto-oncogene frequently mutated in lung cancer). Female A/J, Swiss, and C57BL/6 mice were fed 2 or 4% CS, 1% niacin, or injected with Lov three (Lov-3x) or five (Lov-5x) times per week. After three weeks, serum cholesterol and triglycerides were determined enzymatically. Total, membrane, and cytoplasmic K-ras proteins were determined in lung homogenates by immunoprecipitation followed by Western blotting with a K-ras specific antibody. CS feeding increased membrane K-ras as hypothesized in A/J and C57BL/6 mice, but had no effect in Swiss mice. Lov failed in all three strains to reduce membrane K-ras, and resulted in an increase in total K-ras in A/J and C57BL/6 mice, while again lacking effect in Swiss mice. Niacin had no effect on K-ras protein in any mouse strain. These results differ from our published results for male mice of the same strains, particularly for A/J mice. Increased amounts of K-ras protein in the membrane fraction of A/J females (but not males) treated with either Lov or CS imply that if K-ras were to become mutated, CS could result in increased lung tumorigenesis and Lov would be less likely to be protective in females. In the light of these data, both sexes should be included in future animal and human chemoprevention trials.     

Endpoints and other considerations in phase I studies of targeted anticancer therapy: recommendations from the task force on Methodology for the Development of Innovative Cancer Therapies (MDICT)

Oncology drug development has seen a paradigm shift in the past decade from traditional cytotoxic agents to molecular targeted therapies. Given the different mechanisms and toxicities of these agents, drug development methodology may also require novel approaches. To address emerging issues in oncology drug development the 'Methodology for the Development of Innovative Cancer Therapies' (MDICT) task force was established to provide a forum for academic leaders involved in cancer drug development to discuss methodological issues inherent to the study of targeted anticancer therapy. At the inaugural MDICT meeting in 2006, discussion focused on the most appropriate primary endpoints for first-in-man phase I studies of targeted anticancer agents and organisational issues of such studies. This report summarises the scientific reviews and discussions as well as the recommendations regarding phase I trial design formulated by the MDICT task force.     

Effects of the proteasome inhibitor, bortezomib, on apoptosis in isolated lymphocytes obtained from patients with chronic lymphocytic leukemia.

PURPOSE: Bortezomib is a peptide boronic acid inhibitor of the proteasome developed for cancer therapy. The compound is being evaluated currently in Phase II and III clinical trials. Here we characterized the effects and mechanisms of action of bortezomib in cells obtained from patients with chronic lymphocytic leukemia (CLL). EXPERIMENTAL DESIGN: We exposed isolated CLL lymphocytes from >100 patients to various concentrations of bortezomib or other proapoptotic stimuli, and measured DNA fragmentation by propidium iodide staining and flow cytometry. We characterized the effects of bortezomib on release of apoptosis-associated mitochondrial factors and measured downstream effects on caspase activation using a fluorogenic substrate cleavage assay. We assessed potential effects of the drug on inhibitor of apoptosis protein family apoptosis inhibitors by immunoblotting. Finally, we quantified the effects of bortezomib on apoptosis in 5 patients on a Phase II clinical trial. RESULTS: Bortezomib stimulated apoptosis more rapidly than positive controls (glucocorticoid and fludarabine), although substantial heterogeneity was noted with respect to the concentration of drug required to induce cell death. Bortezomib-induced apoptosis was associated with release of SMAC, apoptosis-inducing factor, and cytochrome c from mitochondria, but the drug did not affect levels of inhibitor of apoptosis protein family cell death inhibitors. Levels of apoptosis were marginally elevated in CLL cells obtained from 2 of 5 fludarabine-refractory patients treated with bortezomib in vivo. CONCLUSION: Our data confirm that bortezomib, like other proteasome inhibitors, has proapoptotic activity in CLL cells.     

Sickness absence in diabetic employees at a large engineering factory.

It is not known whether employees who have diabetes mellitus lose more time from work due to sickness than non-diabetic employees. A study was undertaken to compare sickness absence in 91 diabetic with 91 non-diabetic employees matched for sex, age, and occupation. Although sickness absence was greater in the diabetic group this was not significant. Mean sickness absence for the diabetic employees and controls was 32 v 20 days/year (95% confidence interval -5 to 29 days). Because of the large variability in sickness absence in both diabetic and non-diabetic employees, a study of this size is probably not sufficiently powerful to detect a difference.     

Treatment of previously treated metastatic breast cancer by mitoxantrone and 48-hour continuous infusion of high-dose 5-FU and leucovorin (MFL): low palliative benefit and high treatment-related toxicity

For previously treated advanced breast cancer, there is no standard second-line therapy. Combination chemotherapy with mitoxantrone, high-dose 5-fluorouracil (5-FU) and leucovorin (MFL regimen) had been reported as an effective and well tolerated regimen. From October 1993 to November 1995, we treated 13 patients with previously chemotherapy-treated metastatic breast cancer by mitoxantrone, 12 mg/m2, on day 1 and continuous infusion of 5-FU, 3000 mg/m2, together with leucovorin, 300 mg/m2, for 48 h from day 1 to 2. Each course of chemotherapy was given every 4 weeks. Most of these patients had more than two metastatic sites, with lung metastasis predominant. Seven patients had been treated with anthracycline. Seven patients had previously received radiotherapy and seven had received hormone therapy. Median number of courses of MFL regimen given was six and the median cumulative dose of mitoxantrone was 68.35 mg/m2. One patient had complete response, seven had stable disease, none had partial response and five had progressive disease. The overall objective response rate was 7.6%. The median follow-up period was 14 months. Median survival was 16 months. Median progression-free survival was 5 months. A complete responder had relapse-free survival up to 17 months. Major toxicities were cardiotoxicity and leukopenia. Eight patients were dead in the last follow-up; two of them died of treatment-related toxicity. The MFL regimen achieves little palliative benefit and induces severe toxicity at a fairly high rate. Administration of this regimen to breast cancer patients who have been treated by chemotherapy and those with impaired heart function requires careful attention.