Aggregate Exposure and Cumulative Risk Assessment--Integrating Occupational and Non-occupational Risk Factors.

Occupational exposure limits have traditionally focused on preventing morbidity and mortality arising from inhalation exposures to individual chemical stressors in the workplace. While central to occupational risk assessment, occupational exposure limits have limited application as a refined disease prevention tool because they do not account for all of the complexities of the work and non-occupational environments and are based on varying health endpoints. To be of greater utility, occupational exposure limits and other risk management tools could integrate broader consideration of risks from multiple exposure pathways and routes (aggregate risk) as well as the combined risk from exposure to both chemical and non-chemical stressors, within and beyond the workplace, including the possibility that such exposures may cause interactions or modify the toxic effects observed (cumulative risk). Although still at a rudimentary stage in many cases, a variety of methods and tools have been developed or are being used in allied risk assessment fields to incorporate such considerations in the risk assessment process. These approaches, which are collectively referred to as cumulative risk assessment, have potential to be adapted or modified for occupational scenarios and provide a tangible path forward for occupational risk assessment. Accounting for complex exposures in the workplace and the broader risks faced by the individual also requires a more complete consideration of the composite effects of occupational and non-occupational risk factors to fully assess and manage worker health problems. Barriers to integrating these different factors remain, but new and ongoing community-based and worker health-related initiatives may provide mechanisms for identifying and integrating risk from aggregate exposures and cumulative risks from all relevant sources, be they occupational or non-occupational.

A fatal case of thallium toxicity: challenges in management.

BACKGROUND: Thallium is a highly toxic compound and is occasionally involved in intentional overdoses or criminal poisonings. Accidental poisonings also occur, but are increasingly rare owing to restricted use and availability of thallium. We report a fatal suicidal ingestion of thallium sulfate rodenticide in which multi-dose activated charcoal (MDAC) and Prussian Blue (PB) were both used without changing the outcome. CASE REPORT: A 36 year old man ingested an unknown amount of thallium sulfate grains from an old rodenticide bottle. He presented to an emergency department (ED) 45 minutes later with abdominal pain and vomiting. On examination he was agitated with a blood pressure of 141/60 mmHg and a heart rate of 146 beats per minute (bpm). He received MDAC during his initial ED management and was started on PB 18 hours post arrival; he was intubated on the following day for airway protection. The patient continued to be tachycardic and hypertensive and subsequently developed renal failure. On hospital day three, the patient developed hypotension that did not respond to fluids. The patient required vasopressors and was transferred to a tertiary care center to undergo continuous renal replacement therapy (CRRT). The patient died shortly after his transfer. His last blood thallium concentration was 5369 mcg/L, a spot urine thallium >2000 mcg/L, and a 24- hour urine thallium was >2000 mcg/L. CONCLUSION: Though extremely rare, thallium intoxication can be lethal despite early administration of MDAC and use of Prussian blue therapy. Rapid initiation of hemodialysis can be considered in cases of severe thallium poisoning, to remove additional thallium, to correct acid-base disturbance, or to improve renal function.

Robotic assisted laparoscopic colectomy.

Robotic surgery has evolved over the last decade to compensate for limitations in human dexterity. It avoids the need for a trained assistant while decreasing error rates such as perforations. The nature of the robotic assistance varies from voice activated camera control to more elaborate telerobotic systems such as the Zeus and the Da Vinci where the surgeon controls the robotic arms using a console. Herein, we report the first series of robotic assisted colectomies in Ireland using a voice activated camera control system.

Radiosurgery and fractionated radiation therapy: comparison of different techniques in an in vivo rat glioma model.

To identify histological changes and effects on survival in rats harboring C6 gliomas, the authors compared radiosurgery to different fractionated radiation therapy regimens including doses of calculated biological equivalence. Rats were randomized to control (54 animals) or treatment groups after implantation of C6 glioma cells into the right frontal brain region. At 14 days, treated rats underwent stereotactic radiosurgery (35 Gy to tumor margin; 22 animals), whole-brain radiation therapy (WBRT) (20 Gy in five fractions; 18 animals), radiosurgery plus WBRT (13 animals), hemibrain radiation therapy (85 Gy in 10 fractions; 16 animals) or single-fraction hemibrain irradiation (35 Gy; 10 animals). When compared to the control group (median survival 22 days), prolonged survival was identified after radiosurgery (p < 0.0001), radiosurgery plus WBRT (p < 0.0001), WBRT alone (p = 0.0002), hemibrain radiation therapy to 85 Gy (p < 0.0001), and 35-Gy hemibrain single-fraction irradiation (p = 0.004). Compared to the control group (mean tumor diameter, 6.8 mm), the tumor size was reduced in all treatment groups except WBRT alone. Reduced tumor cell density was exhibited in rats that underwent radiosurgery (p = 0.006) and radiosurgery plus WBRT (p = 0.009) when compared with rats in the control group, a finding not observed after any fractionated regimen. Increased intratumoral edema was identified after radiosurgery (p = 0.03) and combined treatment (p = 0.05), but not after fractionated radiation therapy or 35-Gy single-fraction hemibrain irradiation. In this animal model, the addition of radiosurgery significantly increased tumor cytotoxicity, potentially at the expense of radiation effects to regional brain. We found no difference in survival benefit or tumor diameter in animals that underwent radiosurgery compared to the calculated biologically equivalent regimen of 10-fraction radiation therapy to 85 Gy. The histological responses after radiosurgery were generally greater than those achieved with biologically equivalent doses of fractionated radiation therapy.

Cold-induced alterations in the binding of adrenomedullary nuclear proteins to the promoter region of the tyrosine hydroxylase gene.

It is well documented that cold stress induces a rapid trans-synaptically mediated increase in the relative abundance of rat adrenomedullary tyrosine hydroxylase (TH) mRNA. To investigate the transcriptional mechanisms regulating the cold stress response, we have employed a gel mobility shift assay, using DNA fragments prepared from the proximal 5' flanking region of the bovine TH gene as a heterologous molecular probe. In pilot studies, this region of the bovine TH promoter (nucleotides -246 to +21) was fused to the bacterial reporter gene, chloramphenicol acetyltransferase, and the chimeric construct transfected into human neuroblastoma SK-N-BE(2)-C, hepatoma HepG2, and rat pheochromocytoma PC-12 cells. Results of this analysis indicate that the proximal 5' flanking region of the bovine TH gene contains sufficient information to drive transient reporter gene expression in both human and rat catecholaminergic clonal cell lines. The findings derived from the gel mobility shift studies demonstrate that cold exposure causes rapid and selective alterations in the binding of adrenomedullary nuclear proteins to the proximal 5' flanking region of the TH gene. The most striking cold stress-induced alteration in DNA/nucleoprotein binding occurs in a region of the TH promoter (nucleotides -246 to -189) which contains an element bearing marked sequence similarity to an AP1 binding site and is highly conserved among animal species. This alteration occurs within 1 hr of cold exposure and persists for up to 48 hr after the onset of stress. The results of adrenal denervation experiments indicate that the cold-induced change in DNA/nucleoprotein binding is neurally mediated, requiring intact sympathetic innervation of the gland.(ABSTRACT TRUNCATED AT 250 WORDS)

Radiobiology of radiosurgery: Part II. The rat C6 glioma model.

We developed an experimental animal model to evaluate the potential role of stereotactic radiosurgery for glial neoplasms. Rats were randomized to control or treatment groups after implantation of C6 glioma cells into the right frontal region; 14 days later, 19 rats underwent stereotactic radiosurgical treatment of the induced tumor, using the 4-mm collimator of the gamma unit. Both groups were observed for up to 65 days after implantation. Treated animals had a mean survival of 39.2 days; the 22 control animals lived a mean of 29.4 days before death from tumor growth (P = 0.07). Six treated animals (32%), but only one control animal, survived the full observation period (P = 0.07). The mean tumor diameter in the control group was 9.64 mm; in the radiosurgery group, it was 6.47 mm (P = 0.001). Compared with tumors in control animals, treated tumors had a hypocellular appearance (P less than 0.001) and demonstrated cellular edema (P less than 0.005) under light microscopy, indicating a direct cytotoxic response to treatment. No difference was identified in the amount of tumor necrosis, intratumor hemorrhage, or degree of brain invasion between the two groups. Variations in the maximum treatment dose (30, 40, 50, 70, or 100 Gy) did not result in observed differences in tumor response. This in vivo rat malignant glioma model is a valuable tool to evaluate the tumoricidal effects of single-fraction, focused irradiation. Additional studies are warranted to evaluate dose-response relationships, radiation sensitizers, and use of radiosurgery with other adjuvant treatments.

Effects of parathyroid hormone, calcitonin, and dibutyryl-cyclic AMP on osteoclast area in cultured chick tibia.

Slices of osteoclast-enriched endosteal surfaces of 3 week chick tibia were cultured for 1-3 days. Osteoclasts on the bone surface were made visible by acridine orange fluorescence. Osteoclast area was measured by image analysis. Parathyroid hormone (PTH) caused osteoclasts to increase in area about 40%, and calcitonin (CT) caused a decrease in area also of about 40%. Subsequent addition of dibutyryl cyclic AMP to PTH- or to CT-treated cells resulted in a further change of 40 and 30%, respectively. Application of the cyclic AMP analog alone had no effect. All responses were rapid, occurring in 2-4 minutes.