Patient doses in gamma-intracoronary radiotherapy: the Radiation Burden Assessment Study

PURPOSE: To determine accurately the radiation burden of both patients and staff from intracoronary radiotherapy (IRT) with (192)Ir and to investigate the importance of IRT in the patient dose compared with interventional X-rays. METHODS AND MATERIALS: The Radiation Burden Assessment Study (RABAS) population consisted of 9 patients undergoing gamma-IRT after percutaneous transluminal coronary angioplasty and 14 patients undergoing percutaneous transluminal coronary angioplasty only as the control group. For each patient, the dose to the organs and tissues from the internal and external exposure was determined in detail by Monte Carlo N-particle simulations. Patient skin dose measurements with thermoluminescence dosimeters served as verification. Staff dosimetry was performed with electronic dosimeters, thermoluminescence dosimeters, and double film badge dosimetry. RESULTS: With respect to the patient dose from IRT, the critical organs are the thymus (58 mGy), lungs (31 mGy), and esophagus (27 mGy). The mean effective dose from IRT was 8 mSv. The effective dose values from interventional X-rays showed a broad range (2-28 mSv), with mean values of 8 mSv for the IRT patients and 13 mSv for the control group. The mean dose received by the radiotherapist from IRT was 4 microSv/treatment. The doses to the other staff members were completely negligible. CONCLUSION: Our results have shown that the patient and personnel doses in gamma-IRT remain at an acceptable level. The patient dose from IRT was within the variations in dose from the accompanying interventional X-rays.     

Assessment of carcinogenicity, using PAH-DNA adducts, in workers exposed to polycyclic aromatic hydrocarbons

Introduction

Polycyclic aromatic hydrocarbons (PAH) are environmental contaminants that have been of interest in cancer research for a considerable length of time. DNA adduct formation is considered a marker and indicator for exposure to PAH. The aim of this study was to determine PAH-DNA adduct levels in peripheral blood lymphocytes and urine obtained from workers exposed to PAH, and to evaluate tobacco use, GSTM1 and GSTT1 as possible contributory risk factors.

Material and methods

Our study included a random sample of 66 workers exposed to PAH and 49 non-exposed workers.

Results

PAH-DNA adduct levels of exposed workers were lower than that of the non-exposed group (p<0.05). However, current smoking, GSTM1-negatives, and current smoking with GSTM1-negatives were more frequent in the non-exposed group. In addition, non-exposed workers reported exposure to PAH in their current jobs, as compared with the exposed group (p<0.001). Linear regression analysis identified the levels of benzo-[b]-fluoranthene in the working area as the only significant DNA adduct-forming risk factor (p=0.025).

Conclusion

Further research, with an appropriately large sample size, is highly recommended in measuring PAH-DNA adduct levels and evaluating their relationship with the different types of PAH.     

Experimental study of the carcinogenicity of phenacetin

150 rats and 100 mice were treated subcutaneously (once weekly) and orally (2-5 times a week) with single doses of phenacetin (300-1,000 mg/kg and 800 mg/kg suspended in sunflower oil, respectively). 100 rats and 100 mice in control received sunflower oil alone. Tumor incidence in rats after subcutaneous treatment was 14% and 20%--after oral treatment; in control rats--5 and 5.1%, in experimental mice--33 and 34% and in control mice--5 and 7%, respectively. Mean latent period of tumor induction was noted to be shorter in experimental animals than in controls. Whatever the route of administration, the rats developed precancerous lesions and tumors in the urethra and bladder, hyperplastic changes in the bronchi and adenocarcinoma in lungs as well as single tumors of mammary gland, skin and subcutaneous fat. Hepatocellular hyperplasia, single liver and kidney tumors were observed in mice. Increased tumor incidence in lungs, hemopoietic system and lymphoreticular tissue was higher in experimental mice than in controls. Experimental results evidence weak carcinogenic activity of phenacetin for rats and mice.     

Hypersusceptibility to cisplatin carcinogenicity in metallothionein-I/II double knockout mice: production of hepatocellular carcinoma at clinically relevant doses

Metallothionein (MT) is a high-affinity metal binding protein thought to mitigate the toxicity of various metals. Cisplatin is a widely used cancer chemotherapeutic that is a rodent carcinogen and may have carcinogenic potential in humans. MT seems to reduce cisplatin toxicity by binding the metal compound but how MT deficiency might impact the carcinogenic effects of cisplatin is unknown. Thus, groups (n = 25) of male MT-I/II double knockout (MT-null) or MT wild-type (WT) mice were exposed to a single treatment of cisplatin (5 or 10 mg/kg, i.p.), or left untreated (control) and observed over the next 104 weeks. The doses of cisplatin used equate to only a fraction of the total dose used typically in clinical settings. In cisplatin-treated MT-null mice, a dose-related increase in hepatocellular carcinoma (HCC) occurred (control, 0%; 5 mg/kg, 17%; 10 mg/kg, 36%) that was not seen in WT mice. Similarly, liver carcinoma multiplicity (HCC/liver) was increased markedly by cisplatin but only in MT-null mice, indicating the formation of multiple primaries in MT deficient mice. Harderian gland carcinoma incidence was also increased by cisplatin treatment in MT-null mice but not WT mice. Our results indicate that MT-null mice are hypersusceptible to the hepatocarcinogenic effects of cisplatin, and poor MT expression may be a predisposing factor for cisplatin-induced secondary tumors after chemotherapy.     

Experimental study of ortho-toluidine carcinogenicity

Ortho-toluidine carcinogenicity has been tested in chronic experiments using mice, rats and dogs. Tumors were induced in 19% of mice (lung and kidney adenomas, leukemia), rats--40% (subcutaneous fat tumors, mammary fibroadenomas, leukemia, renal tumors and hepatic sarcoma). Bladder tumors developed in two dogs after 9 and 10 years of experiment. Both literature and experimental evidence point to o-toluidine as a hazard to humans.     

The carcinogenicity of two diazadibenzopyrenes

1,12-Diazadibenzo(a,i)pyrene (I), an isostere of the extremely potent carcinogen dibenzo(a,i)pyrene, also displays carcinogenicity although to a considerably lesser degree than the latter compound. While dibenzo(a,h)pyrene is known to be distinctly less active than dibenzo(a,i)pyrene, surprisingly 4,11-diazadibenzo(a,h)pyrene (II) shows a greater activity than I. Another hexacyclic diaza-hydrocarbon, 4,12-diazadibenzo(g,p)chrysene (III), which is devoid of a meso-phenanthrenic region, proved totally inactive.     

Inter-species comparisons of carcinogenicity.

The carcinogenicity of 250 chemicals in 2 species, usually the rat and the mouse, was obtained from the published literature through 3 independent sources. Of the 250 compounds listed, 38% were non-carcinogenic in both rats and mice, and 44% were carcinogenic in both species. A total of 43 compounds had different results in the two species, 21 (8%) being carcinogenic in mice only, 17 (7%) in rats only and 5 (2%) having differing results from other species. A comparison of the major target organs affected by chemicals carcinogenic in both species revealed that 64% of the chemicals studied produced cancer at the same site. This comparison of carcinogenic activity in 2 species suggests that extrapolation from results in a single-animal study to man may be subject to substantial errors.     

A case of chronic adult T-cell leukemia benefited by small doses of MEPP

A 59-year-old man diagnosed as a chronic ATL with cutaneous invasion, was treated with small doses of CPM, ADM, VDS and PSL regimens according to CHOP. The treatment was successful and achieved PR at the first stage of the therapy, but it became refractory later. He was then treated with small MEPP (MXT, VP-16, CDDP and PSL) as the salvage therapy for non-Hodgkin's lymphoma. This case suggested that small MEPP might be a useful combination chemotherapy for ATL.     

Response of fibrosarcoma cell subpopulations to small doses of radiation delivered in situ

The survival of cells from 2 tumor subpopulations after γ-ray doses ranging from 1 to 19 Gy was determined using a lung colony assay. Methylcholanthrene-induced fibrosarcomas grown in the hind legs of C3H/Kam pathogen-free mice were irradiated in situ when the tumors were 8–10 mm in diameter. Single cell suspensions prepared from excised tumors were separated on a linear density gradient, and the clonogenicity of predominantly oxic Band 2 (density 1.08 g/cm²) and predominantly bypoxic Band 4 (density 1.14 gm/cm³) cells was measured. The surviving fraction of cells after doses of 1, 2, and 3 Gy was estimated from that measured after total doses of 5 Gy = 5 × 1 Gy, 10 Gy = 5 × 2 Gy, and 15 Gy = 5 × 3 Gy, under the assumption of equal effect per fraction (checked by estimating survival at 3 Gy after different numbers of fractions). Very little curvature was evident in the survival curves of Band 2 and Band 4 cells (β/α = .013–.034 Gy^?1). The initial segment of the survival curve of the predominantly oxic Band 2 cells was steeper (₁D₀ = 3.6 Gy) than that of the predominantly hypoxic Band 4 cells (₁D₀ = 5.2 Gy); both remained linear over a large range, to doses in excess of 3 Gy. These results imply that these tumor subpopulations will be insensitive, in their response to multifractionated regimens, to changes in size of dose per fraction in the range 0 to 3 Gy, a trait shared by two acutely responding normal tissues (marine testis and jejunum).     

In-vivo carcinogenicity of 2-nitro-oxaphenalenes

2-Nitro-oxaphenalenes are synthetic chemicals which were synthesized in the authors' laboratory. They are the most efficient mutagenic compounds on mammalian cells in culture. They are chemically related to the nitro-naphthofuran family by the displacement of the heterocycle on the naphthalene ring. Since nitro-naphthofurans have a strong mutagenic activity in bacterial tests without metabolic activation and are active in-vivo carcinogens, the purpose of this study was to demonstrate the carcinogenic activity of two 2-nitro-oxaphenalenes. The two compounds were injected s.c. into Wistar rats initially 6-weeks-old. They were dissolved in dimethylsulfoxide (DMSO) at a concentration of 1 mg/ml. A s.c. injection of 0.5 ml containing 0.5 mg of carcinogen was given once a week in the neck of each animal tested. Five control animals were not injected and five animals received 0.5-ml injection of DMSO every week to serve as a control. The animals developed tumors only at the site of injection. The tumors were classified as high grade fibrosarcomas. This experiment demonstrates that: (i) 2-nitro-oxaphenalenes are very active in-vivo carcinogens in rats; (ii) there is a good correlation between the high mutagenic activity especially in mammalian tests and the strong carcinogenicity of the compounds; and (iii) the presence of a 6-methoxy group increases by two-fold the carcinogenic potential.