Total Body Exposure Research Articles

Naphthalene and its biomarkers as measures of occupational exposure to polycyclic aromatic hydrocarbons.

Polycyclic aromatic hydrocarbons (PAH) include compounds with two or more fused benzene rings, many of which are carcinogens. Industrial sources produce hundreds of PAH, notably in the coke- and aluminium-producing industries. Because PAH are distributed at varying levels between gaseous and particulate phases, exposure assessment has been problematic. Here, we recommend that occupational exposures to naphthalene be considered as a potential surrogate for occupational PAH exposure for three reasons. Naphthalene is usually the most abundant PAH in a given workplace; naphthalene is present almost entirely in the gaseous phase and is, therefore, easily measured; and naphthalene offers several useful biomarkers, including the urinary metabolites 1- and 2-hydroxynaphthalene. These biomarkers can be used to evaluate total-body exposure to PAH, in much the same way that 1-hydroxypyrene has been applied. Using data from published sources, we show that log-transformed airborne levels of naphthalene are highly correlated with those of total PAH (minus naphthalene) in several industries (creosote impregnation: Pearson r= 0.815, coke production: r= 0.917, iron foundry: r= 0.854, aluminium production: r= 0.933). Furthermore, the slopes of the log-log regressions are close to one indicating that naphthalene levels are proportional to those of total PAH in those industries. We also demonstrate that log-transformed urinary levels of the hydroxynaphthalenes are highly correlated with those of 1-hydroxypyrene among coke oven workers and controls (r= 0.857 and 0.876), again with slopes of log-log regressions close to one. These results support the conjecture that naphthalene is a useful metric for occupational PAH exposure. Since naphthalene has also been shown to be a respiratory carcinogen in several animal studies, it is also argued that naphthalene exposures should be monitored per se in industries with high levels of PAH.

Radiation-induced second cancers: the impact of 3D-CRT and IMRT

Information concerning radiation-induced malignancies comes from the A-bomb survivors and from medically exposed individuals, including second cancers in radiation therapy patients. The A-bomb survivors show an excess incidence of carcinomas in tissues such as the gastrointestinal tract, breast, thyroid, and bladder, which is linear with dose up to about 2.5 Sv. There is great uncertainty concerning the dose– response relationship for radiation-induced carcinogenesis at higher doses. Some animal and human data suggest a decrease at higher doses, usually attributed to cell killing; other data suggest a plateau in dose. Radiotherapy patients also show an excess incidence of carcinomas, often in sites remote from the treatment fields; in addition there is an excess incidence of sarcomas in the heavily irradiated in-field tissues. The transition from conventional radiotherapy to three-dimensional conformal radiation therapy (3D-CRT) involves a reduction in the volume of normal tissues receiving a high dose, with an increase in dose to the target volume that includes the tumor and a limited amount of normal tissue. One might expect a decrease in the number of sarcomas induced and also (less certain) a small decrease in the number of carcinomas. All around, a good thing. By contrast, the move from 3D-CRT to intensity-modulated radiation therapy (IMRT) involves more fields, and the dose– volume histograms show that, as a consequence, a larger volume of normal tissue is exposed to lower doses. In addition, the number of monitor units is increased by a factor of 2 to 3, increasing the total body exposure, due to leakage radiation. Both factors will tend to increase the risk of second cancers. Altogether, IMRT is likely to almost double the incidence of second malignancies compared with conventional radiotherapy from about 1% to 1.75% for patients surviving 10 years. The numbers may be larger for longer survival (or for younger patients), but the ratio should remain the same.

Pharmacokinetics and Pharmacodynamics of Intravenous Levofloxacin in Patients with Early-Onset Ventilator-Associated Pneumonia

To investigate the pharmacokinetics of levofloxacin and the pharmacokinetic-pharmacodynamic appropriateness of its total body exposure in patients in the intensive care unit (ICU) treated for early-onset ventilator-associated pneumonia (VAP) with intravenous levofloxacin 500mg twice daily. Prospective non-blinded pharmacokinetic-pharmacodynamic study. Ten critically ill adult patients with normal renal function. Blood and urine samples were collected at appropriate times during a 12-hour administration interval at steady state. Levofloxacin concentrations were determined by high-performance liquid chromatography. Clinical and microbiological outcomes were assessed. Levofloxacin pharmacokinetics were only partially comparable with those obtained from literature data for healthy volunteers. Area under the concentration-time curve (AUC(tau)) over the 12-hour dosage interval was about 30-40% lower than in healthy volunteers (33.90 vs 49.60 mg. h/L). The reduced exposure may be due to a greater clearance of levofloxacin (0.204 vs 0.145 L/h/kg [3.40 vs 2.42 mL/min/kg]), leading to a shorter elimination half-life (5.2 vs 7.6 hours). Cumulative urinary excretion during the 12-hour dosage interval confirmed the greater excretion of unchanged drug in these patients compared with healthy subjects (76% vs 68%). Coadministered drugs used to treat underlying diseases (dopamine, furosemide, mannitol) may at least partially account for this enhanced elimination in critically ill patients. Intravenous levofloxacin 500mg twice daily ensured a median C(max)/MIC (maximum plasma concentration/minimum inhibitory concentration) ratio of 102 and a median 24-hour AUC/MIC ratio of 930 SIT(-1). h (inverse serum inhibitory titre integrated over time) against methicillin-sensitive Staphylococcus aureus and Haemophilus influenzae. The overall success rate of the assessable cases was 75% (6/8). Bacterial eradication was obtained in all of the assessable cases (8/8), but a superinfection (Acinetobacter anitratus,Pseudomonas aeruginosa) occurred in three cases. The findings support the suitability of intravenous levofloxacin 500mg twice daily in the treatment of early-onset VAP in ICU patients with normal renal function. Levofloxacin may represent a valid alternative to non-pseudomonal beta-lactams or aminoglycosides in the empirical treatment of early-onset VAP. However, further larger studies are warranted to investigate its efficacy.

Hematopoietic recovery following autologous bone marrow transplantation in a nonhuman primate: effect of variation in treatment schedule with PEG-rHuMGDF.

Mathematical modeling of pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) pharmacokinetics (PK) and pharmacodynamics (PD) suggest that variations in the PEG-rHuMGDF treatment schedule could reduce the severity and duration of thrombocytopenia following myeloablation and bone marrow transplant (BMT). We tested this hypothesis in a rhesus monkey model of autologous (Au) bone marrow-derived mononuclear cell (BM-MNC) transplantation following lethal myeloablation. On day 0, animals were myeloablated by total body exposure to 920 cGy, 250 kVp x-irradiation (TBI). Four cohorts of animals were infused with 1 x 10(8) AuBM-MNC/kg body weight within 2 hours of TBI. The AuBMT-alone cohort received no cytokine, the daily dosage cohort received PEG-rHuMGDF (2.5 micro g/kg/day, s.c.) post TBI and AuBMT, and the pre/post-transplant cohort received PEG-rHuMGDF (2.5 micro g/kg/day, s.c.) pre (day -9 to day -5) and post TBI and AuBMT. The post-transplant PEG-rHuMGDF administration in the above cohorts was begun on day 1 post TBI and continued until platelet counts reached 200,000 micro l (range, 15-31 days). Another group received PEG-rHuMGDF (300 micro g/kg/day, s.c.) on days 1 and 3 only following TBI and AuBMT. The TBI controls received neither AuBMT nor cytokine therapy. In this model of AuBMT, with regard to the PEG-rHuMGDF administration schedule, the daily dosage of the post-transplant cohort did not significantly improve platelet recovery; the pre/post-transplant schedule and an abbreviated high-dosage, post-transplant schedule (days 1 and 3) significantly improved the duration and nadir of thrombocytopenia and platelet recovery. These data confirm predictions from PK/PD modeling of PEG-rHuMGDF that thrombocytopenia is preventable following AuBMT.

Importance of respiratory exposure to pesticides among agricultural populations.

In the majority of cases, respiratory exposure accounts for a small fraction of total body exposure to pesticides; however, higher volatility pesticides pose a greater risk for exposure, particularly in enclosed spaces and near application sites. In 2000, nearly 22 million pounds of active ingredients designated as toxic air contaminants (TACs) were applied as pesticides in California (combined agricultural and reportable non-agricultural uses; California Department of Pesticide Regulation, 2001a, Summary of Pesticide Use Report Data, 2000, Sacramento, CA: author). Agricultural workers and agricultural community residents are at particular risk for exposure to these compounds. The TAC program in California, and more recently the federal Clean Air Act amendments, have begun to address the exposures of these groups and have promulgated exposure guidelines that are, in general, much more stringent than the Occupational Safety and Health Administration (OSHA) and American Conference of Governmental Industrial Hygienists (ACGIH) worker exposure guidelines. Choosing lower volatility pesticides, lower concentrations of active ingredients, and handling equipment designed to minimize exposure can often reduce worker respiratory exposures significantly. The use of personal protective equipment, which would be facilitated by the development of more ergonomic alternatives, is important in these higher respiratory exposure situations. Finally, in the case of community residents, measures taken to protect workers often translate to lower ambient air concentrations, but further study and development of buffer zones and application controls in a given area are necessary to assure community protection.

Structure and function of bone marrow hemopoiesis: mechanisms of response to ionizing radiation exposure.

It is the purpose of this presentation to review the unique structure and function of bone marrow anchored hematopoiesis in their significance for its response mechanisms to an exposure to ionizing radiation. The ultimate objective of bone marrow hematopoiesis is to maintain in the peripheral blood a constant level of the different blood cell types (erythrocytes, granulocytes, platelets, lymphocytes, etc.). All of them have their particular turnover kinetics (such as granulocytes 120 x 10(9)/d, erythrocytes 200 x 10(9)/d or thrombocytes 150 x 10(9)/d), are semi-autonomous in their steady state regulatory mechanisms and dependent on a life-long supply of mature cells from a stem cell pool with unlimited replicative and pluripotent differentiative potential. The present knowledge of hematopoietic cellular renewal is the result of years of basic experimental and clinical studies using radionuclides in various metabolic forms including (59)Fe, (32)P (DF (32)P), (51)Cr, (131)I, (60)Co, (3)H ((3)HTdR) and (14)C ((14)CTdR). To understand the physiology but in particular the radiation-pathophysiology, it is essential to recognize in detail the infrastructure of the bone marrow as a distinct unit. Indispensable for a life-long cell production is the capsule of the marrow - the bone cortex -, the arterial supply of blood connected to the sinusoidal microvascular architecture with its sinusoids contorti and recti as well as the central (cell collecting) sinusoids. It is further of importance to recognize the significance of nerval regulation of blood flow, characterized by myelinated and unmyelinated nerve fibers. The type of unique lining cells of the sinusoids is the prerequisite for the cell traffic between the hemopoietic parenchyma and the blood. This in turn cannot be achieved without an alternative opening and closing of the sinusoidal segments which - in turn - requires a rigid long capsule to assure an - in toto - constant volume of each bone marrow unit. If a bone marrow unit is exposed to ionizing radiation, a perturbance of the balance between cellular growth pressure and blood flow dynamics can be observed, resulting in a special type of bone marrow hemorrhage and an "excess cell loss" that may result in an non-thrombopenic exhaustion of the stem cell pool. Of great importance is the question as to the mechanisms that allow the bone marrow hemopoiesis to act as one cell renewal system although the bone marrow units are distributed throughout more than 100 bone marrow areas or units in the skeleton. The observation that "the bone marrow" acts and reacts as "one organ" is due to the regulatory mechanisms: the humeral factors (such as erythropoietins, granulopoietins, thrombopoietins etc.), the nerval factors (central nervous regulation) and cellular factors (continuous migration of stem cells through the blood to assure a sufficient stem cell pool size in each bone marrow "sub-unit"). It should be recalled that the bone marrow functions as a physiological chimera and becomes established by the hematogeneic seeding of stem cells to a mesenchymal matrix during embryogenesis. The repopulation of the bone marrow after partial body irradiation, after strongly inhomogeneous radiation exposure or after total body exposure with stem cell transplantation can well be considered as a repetition of the embryogenesis of bone marrow hemopoiesis with the key element of stem cells migrating via the blood to stromal sites of the marrow prepared to accept stem cells to home and start their replication and differentiation if the micro-environmental quality permits. In summary, the radiation biology of bone marrow hemopoiesis requires a thorough understanding of the physiology and pathophysiology of structure, function and regulation not only of the process of cellular renewal but also of the intricate infrastructure.

A Dirichlet Tessellation-based Sampling Scheme for Measuring Whole-body Exposure

Dermal sampling can be conducted using small pads or patches attached to various areas of the skin or clothing, or by using a whole-body coverall. Both techniques are recognized standardized methods for collecting chemicals. Patch sampling is simple to perform and inexpensive to analyse compared with an entire overall, but may require some user intervention. Extrapolation from a small sampled area to the total body area can lead to inaccurate estimates of total body exposure because of a lack of uniformity of deposition. Whole-body overall analysis eliminates the problems associated with using patches and gives a more accurate estimate of total body exposure. Therefore, if it were possible to measure the whole-body overall accurately and quickly, we would have a better assessment of dermal exposure. In this study we develop a working protocol using a standardized approach, to measure the contamination over an entire overall. The protocol takes into account size differences and establishes a reproducible pattern of sampling in order to map the distribution of contamination over each overall. The working protocol has been applied to 10 overalls collected from companies using copper-based biocides. A portable X-ray fluorescence spectrometer (PXRF) was used to measure the copper in the biocide. The exposure estimate from the PXRF results uses an averaging scheme based on the Dirichlet tessellation of the sampling locations. This allows unbiased estimates to be obtained from a complex sampling scheme that allocates more measurements to areas of high exposure. The Dirichlet tessellation method has been compared to the patch sampling method and the conventional total digestion of the entire overall method. Using the whole-suit digestion method as the benchmark, exposures ranged from 92.0 to 5848.5 mg. Mean absolute percentage errors (from the benchmark acid digestion of the whole suit) varied from approximately 20% for the Dirichlet-based PXRF method to 60% for the patch methods. The patch methods underestimated the true dermal exposure (-28 to -82% for acid digestion of the patches). Analysis of this data indicates that the Dirichlet PXRF method gives a more accurate estimate of whole-body contamination than the patch method. Furthermore, the 104 measurements give a much greater spatial resolution to the exposure data than analysis of the whole overall or patches by inductively coupled plasma-atomic emission mass spectrometry (ICP-AES). This detailed knowledge of the pattern of deposition on the body is of potential importance in chemical risk assessments.

Total body exposure to ultraviolet radiation does not influence plasma levels of immunoreactive beta-endorphin in man.

A growing number of reports support evidence of proopiomelanocortin (POMC)-derived peptides in human skin cells, although not consistently. Also the effect of ultraviolet radiation (UVR) on cutaneous and plasma levels of these POMC peptides has not been established unequivocally. We hypothesized that production of beta-endorphin (betaE) may explain the sense of well-being many people experience when sun-bathing. The aim of the present study was to investigate whether exposure of the skin to UVR elevates plasma betaE. Healthy volunteers (n=26) received a single, weighted dose of 15 J/cm2 of UVA. Several times during the hour following irradiation, plasma betaE- immunoreactivity (betaE-IR) was determined by radioimmunoassay. The effect of repeated exposure was assessed in 35 patients treated with UVB, UVA, or UVA-1. Plasma ACTH-IR was monitored in parallel. Overall, plasma levels of betaE-IR and ACTH-IR showed no significant changes during the experiment, indicating that these peptides are not influenced by single or repeated exposures to UVR of different wavelengths. On the basis of these results, the skin does not appear to contribute significantly to the levels of circulating betaE or ACTH. These data offer no support for the hypothesis that exposure to UVR leads to an increased concentration of circulating betaE, which could contribute to the feeling of well-being that often accompanies sun-bathing.

Total body exposure to ultraviolet radiation does not influence plasma levels of immunoreactive β‐endorphin in man

Background/Aims: A growing number of reports support evidence of proopiomelanocortin (POMC)‐derived peptides in human skin cells, although not consistently. Also the effect of ultraviolet radiation (UVR) on cutaneous and plasma levels of these POMC peptides has not been established unequivocally. We hypothesized that production of β‐endorphin (βE) may explain the sense of well‐being many people experience when sun‐bathing. The aim of the present study was to investigate whether exposure of the skin to UVR elevates plasma βE.Method: Healthy volunteers (n=26) received a single, weighted dose of 15 J/cm2 of UVA. Several times during the hour following irradiation, plasma βE‐ immunoreactivity (βE‐IR) was determined by radioimmunoassay. The effect of repeated exposure wasassessed in 35 patients treated with UVB, UVA, or UVA‐1. Plasma ACTH‐IR was monitored in parallel.Results: Overall, plasma levels of βE‐IR and ACTH‐IR showed no significant changes during the experiment, indicating that these peptides are not influenced by single or repeated exposures to UVR of different wavelengths.Conclusion: On the basis of these results, the skin does not appear to contribute significantly to the levels of circulating βE or ACTH. These data offer no support for the hypothesis that exposure to UVR leads to an increased concentration of circulating βE, which could contribute to the feeling of well‐being that often accompanies sun‐bathing.

Early menarche and adult height: Reprise of the hare and the tortoise?

Early menarche and adult height: Reprise of the hare and the tortoise?

Identification of dermal exposure pathways in the rubber manufacturing industry

Current existing dermal exposure assessment strategies are predominantly based on regulatory protocols. In order to develop effective and efficient strategies more data driven approaches are needed. In a recently developed conceptual model for dermal exposure, compartments, barriers and mass transport processes relevant for dermal exposure were described. We systematically applied this conceptual model to the rubber manufacturing industry to assess dermal exposure to cyclohexane soluble matter (CSM) and used quantitative data to design an exposure assessment strategy. Identification of the spatial distribution of the dermal contamination showed high CSM surface concentrations for the upper body. Moreover, because of the high correlation between dermal exposure at the wrist and calculated total body exposure (r=0.89, P<0.01) an exposure assessment strategy based on only one pad sampler was employed to estimate CSM surface concentrations in the skin contaminant layer. Qualitative and quantitative evaluation of the relevant compartments and related mass transport processes demonstrated the importance of deposition of airborne contaminants and direct transfer of contaminants from sources and surfaces to the skin contaminant layer. Interestingly, the importance of the different exposure pathways varied considerably between production functions. The use of a model driven exposure assessment strategy in the rubber manufacturing industry revealed relevant skin regions, compartments and mass transport processes and enabled development of an effective and efficient strategy for dermal exposure assessment and hazard control in this particular occupational setting.

Identification of dermal exposure pathways in the rubber manufacturing industry

Current existing dermal exposure assessment strategies are predominantly based on regulatory protocols. In order to develop effective and efficient strategies more data driven approaches are needed. In a recently developed conceptual model for dermal exposure, compartments, barriers and mass transport processes relevant for dermal exposure were described. We systematically applied this conceptual model to the rubber manufacturing industry to assess dermal exposure to cyclohexane soluble matter (CSM) and used quantitative data to design an exposure assessment strategy. Identification of the spatial distribution of the dermal contamination showed high CSM surface concentrations for the upper body. Moreover, because of the high correlation between dermal exposure at the wrist and calculated total body exposure (r=0.89, P<0.01) an exposure assessment strategy based on only one pad sampler was employed to estimate CSM surface concentrations in the skin contaminant layer. Qualitative and quantitative evaluation of the relevant compartments and related mass transport processes demonstrated the importance of deposition of airborne contaminants and direct transfer of contaminants from sources and surfaces to the skin contaminant layer. Interestingly, the importance of the different exposure pathways varied considerably between production functions. The use of a model driven exposure assessment strategy in the rubber manufacturing industry revealed relevant skin regions, compartments and mass transport processes and enabled development of an effective and efficient strategy for dermal exposure assessment and hazard control in this particular occupational setting.

Significance of excursions of intake above the acceptable daily intake: effect of time and dose in developmental toxicology.

Three major factors to be considered in assessing the possible effects on developmental toxicology of excursions above the acceptable daily intake (ADI) are discussed. If maternal toxicity occurs at lower doses than developmental toxicity, then there may be adequate protection for the fetus if the mother is protected. In other cases, the first adverse developmental effects are usually small and reversible changes in fetal weight and it is unlikely that brief excursions, for a few days, above the ADI, would induce changes in final birth weight. The importance of excursions above the ADI on teratogenic responses would likely depend on the mechanism of teratogenesis and whether the agent acted primarily as a result of a high peak plasma level, a Cmax effect, or depended more on the total body exposure, an area under the curve (AUC) effect. This type of information is usually not available from current safety study designs. Finally, the temporal equivalence factors must be taken into account. There are 10- to 100-fold differences in time span for pre- and postnatal development up to sexual maturity, in rodents compared with humans. This can be contrasted with the relatively small pharmacokinetic differences, perhaps of up to 2- or 3-fold in plasma levels of chemicals with the same administered dose in the two species. Thus, single episodes of high chemical exposure have greater opportunity to produce permanent effects on development in rodents compared with humans. The limited evidence from acute poisonings in pregnant women tends to support this hypothesis and it seems unlikely that occasional excursions by women above the ADI would result in developmental toxic effects.

Protective effect of low frequency low energy pulsing electromagnetic fields on acute experimental myocardial infarcts in rats.

This series of experiments assesses the effect of exposure to low-frequency pulsing electromagnetic fields (PEMFs) in 340 rats with acute experimental myocardial infarcts. The left anterior descending artery was ligated with suture thread, and the rats underwent total body exposure to PEMFs until they were killed. Twenty-four hours after surgery, the necrotic area was evaluated by staining with triphenyltetrazolium chloride. A significant reduction of the necrotic area was observed in the animals exposed to PEMFs compared with the nonexposed controls. Exposure for up to 6 days does not appear to affect the area of necrosis, although in exposed animals an increase of vascular invasion of the necrotic area is observed: 24.3 % as against 11.3 % in controls. No effect on the necrotic area size from exposure was found when the left anterior descending artery was occluded for 60 min, followed by reperfusion. The results reported show that exposure to PEMFs is able to limit the area of necrosis after an acute ischemic injury caused by permanent ligation of the left anterior descending artery. These data are in agreement with the protective effect of PEMFs observed on acute ischemia in skin free flaps in rats and in cerebral infarcts in rabbits.

Pharmacokinetic variability and strategy for therapeutic drug monitoring of saquinavir (SQV) in HIV-1 infected individuals.

To investigate the pharmacokinetic profile of the protease inhibitor saquinavir (SQV) after multiple doses in HIV-positive patients and to evaluate the possibility of predicting total body exposure of SQV from concentrations determined at single time points. Twenty HIV-positive patients on steady-state treatment with SQV (Hard-Gel-Capsule, Invirase(R)) were enrolled in this study. Serial blood samples were obtained during a dosing interval. SQV plasma concentrations were determined by high performance liquid chromatography (h.p.l.c.) and pharmacokinetic parameters were determined by noncompartmental techniques. There was a marked interindividual variability in SQV pharmacokinetic parameters with a 11-fold variability in total systemic exposure to SQV, as expressed by AUC(0,8h) values (range: 268-3009 ng ml-1 h, CV: 69%). The oral clearance shows an interindividual CV of 75%. A strong correlation (r=0.94) was found between SQV plasma concentration at 3 h (C3 h ) and AUC(0,8h). This study shows that C3 h is a good predictor for total body exposure of SQV and might be useful to predict SQV disposition in HIV-positive patients on steady-state treatment.

An abbreviated area-under-the-curve monitoring for tacrolimus in patients with liver transplants.

This study aims to assess the predictability of individual tacrolimus (FK) concentrations at different time points for the area under the curve (AUC) and to find the best sampling time for the abbreviated AUC to predict the total body exposure of FK. A total of 23 FK blood concentration versus time profiles (11 blood samples per 12 hours) was studied in 12 stable patients with liver transplants at steady state. Each AUC was calculated by the trapezoidal rule, and the relationship between individual concentrations or abbreviated AUC and total AUC was determined by linear regression. The trough concentrations from the morning dose predict AUC better than the trough concentration from the evening dose (r2 = 0.71 for morning dose and r2 = 0.35 for evening dose). In the case of single drug concentration, the 4-hour concentration could predict the total AUC reasonably well (r2 = 0.73). From stepwise multiple regression, the abbreviated AUC at 1, 2.5, 6, and 9 hours could predict the total AUC most accurately (r2 = 0.99). This study shows that the four levels at 1, 2.5, 6, and 9 hours or 1, 4, and 12 hours as an abbreviated AUC is as good as a full pharmacokinetic study. Alternatively, 4-hour concentration is a good predictor of the total body exposure of FK in the stable patients with liver transplants.

Detection of total- and partial-body irradiation in a monkey model: a comparative study of chromosomal aberration, micronucleus and premature chromosome condensation assays

Purpose: To investigate the efficacy of three cytogenetic methods (dicentrics, micronuclei (MN) and premature chromosome condensation (PCC) analysis) for assessment of the unirradiated fraction and the persistence of damage after total-body (TB) and partial-body (PB) irradiation of rhesus monkeys (Macaca mulatta) . Materials and methods: Animals were exposed to X-rays (5 Gy), either TB or PB, with about 6 % of marrow cells shielded. Blood samples were collected at different times after exposure, i.e. 1, 3 and 7 days, and cultures were set up for the different cytogenetic endpoints. In addition, blood count analysis was performed before and after irradiation. Results: Blood count analysis was not suitable for discriminating between TB and PB exposure. By using Poisson or overdispersion distribution as the basis, it was not possible to distinguish TB from PB irradiation when dicentric chromosomes and MN were analysed. PCC analysis, in contrast, showed a Poisson distribution after TB exposure and overdispersion after PB exposure. Using the PCC assay, reliable dose estimates could be obtained up to 7 days after irradiation. Conclusions: For dicentrics and MN, shielding of 6 % of bone marrow cells was found to be too small to estimate the unirradiated fraction accurately. The PCC technique was useful for dose assessment and the inhomogeneous exposure of 6 % was detected within a short period of time after exposure.

Intracoronary low-dose beta-irradiation inhibits neointima formation after coronary artery balloon injury in the swine restenosis model.

Neointima formation contributing to recurrent stenosis remains a major limitation of percutaneous transluminal angioplasty. Endovascular low-dose gamma-irradiation has been shown to reduce intimal thickening (hyperplasia) after balloon overstretch injury in pig coronary arteries, a model of restenosis. The objective of this study was to determine whether the use of a beta-emitting radioisotope for this application would have similar effects and to examine the dose-response relations with this approach. Normal domestic pigs underwent balloon overstretch injury in the left anterior descending and left circumflex and coronary arteries. A flexible catheter was introduced by random assignment into one of these arteries and was afterloaded with a 2.5-cm ribbon of encapsulated 90Strontium/90Yttrium sources (90Sr/Y, a pure beta-emitter). It was left in place for a period of time sufficient to deliver one of four doses: 7, 14, 28, or 56 Gy, to a depth of 2 mm. Animals were killed 14 days after balloon injury, the coronary vasculature was pressure-perfusion fixed, and histomorphometric analysis of arterial cross sections was performed. All arteries treated with radiation demonstrated significantly decreased neointima formation compared with control arteries. The ratio of intimal area to medial fracture length was inversely correlated with increasing radiation dose: control (no radiation), 0.47; 7 Gy, 0.34; 14 Gy, 0.20; 28 Gy, 0.08; and 56 Gy, 0.02 (r = -.78, P < .000001). Scanning electron microscopy demonstrated a confluent layer of endothelium-like cells both in control and in 14 Gy-irradiated arteries. There was neither evidence of significant necrosis nor excess fibrosis in the media, adventitia, or perivascular space of the coronary arteries or adjacent myocardium in the irradiated groups. Furthermore, the exposure to the staff and the total body exposure to the pig with the beta source was a small fraction of the dose previously measured and calculated with 192Ir, a gamma-emitting radioisotope. Administration of endovascular beta-radiation to the site of coronary arterial overstretch balloon injury in pigs with 90Sr/Y is technically feasible and safe. Radiation doses between 7 and 56 Gy showed evidence of inhibition of neointima formation. A dose-response relation was demonstrated, but no further inhibitory effect was seen beyond 28 Gy. These data suggest that intracoronary beta-irradiation is practical and feasible and may aid in preventing clinical restenosis.

Hemoglobin adducts and urine metabolites of 4,4′-methylenedianiline after 4,4′-methylenediphenyl diisocyanate exposure of rats

4,4′-Methylenediphenyl diisocyanate (MDI) is a very important component in the production of Polyurethane. In a long-term experiment, designed to determine the carcinogenic and toxic effects of MDI, rats were exposed chronically for 3 and 12 months, to 0.0 (control), 0.26, 0.70 and 2.06 mg MDI/m 3 as aerosols. Hemoglobin adducts and urine metabolites of MDI were determined at the different doses in order to develop methods to biomonitor workers exposed to MDI and to assess a risk resulting from such exposure. Hemoglobin adducts and urine metabolites of 4,4′-methylenedianiline (MDA) were found in all rats, including controls. MDA and N-acetyl-MDA (AcMDA) were quantified by GC-MS after derivatization with heptafluorobutyric anhydride. The dose-response relationships for hemoglobin adducts and urine metabolites were non-linear over this dose range. In urine, free AcMDA and MDA were found after base extraction. The amount of MDA present in urine and to a lesser extent the AcMDA found in urine correlate well with the corresponding amount determined as hemoglobin adducts for all dose groups. In order to release MDA from possible conjugates of MDA and AcMDA, urine was treated under strong acidic conditions. Following this procedure higher MDA levels were found than the sum of MDA and AcMDA from mild base hydrolysis. Similar results were obtained with the rats exposed for 3 and 12 months, indicating that a steady state had been reached by 3 months. In order to perform further investigations of the bronchoalveolar lavage fluid one group of animals was given a 1 week recovery period before sacrifice. Hemoglobin adducts from these animals showed a decrease of approximately 40% for all dose groups. According to the lifetime of rat erythrocytes the levels of hemoglobin adducts should have decreased by only 22%. This suggests that the erythrocytes with modified hemoglobin have a shorter lifespan. In order to exclude the possibility that hemoglobin adducts may have resulted from ingestion of hydrolyzed MDI via licking of the fur, a single dose experiment with rats exposed through the nose only or with the whole body was carried out. The only difference observed between these two exposure regimes was that the hemoglobin adduct levels of AcMDA after nose only exposure were significantly higher than after total body exposure. The presence of AcMDA in urine and as a hemoglobin adduct indicates that MDA was bioavailable after MDI exposure. The presence of MDA may contribute significantly to the carcinogenic potential of MDI, since MDA has been shown to be carcinogenic in animals.

Choice of detectors for in vivo elemental analysis by counting natural and neutron-induced gamma rays for medical applications

Body fat is measured by detecting C and O in vivo through fast neutron inelastic scattering. A sealed DT neutron generator is used for the pulsed (4–10 kHz) production of fast neutrons. Carbon and oxygen are detected by counting the 4.44 and 6.13 MeV gamma rays resulting from the inelastic scattering of the fast neutrons from 12C and 16O. Large Bi 4Ge 3O 12 (BGO) crystal detectors (127 × 76 mm) are used for the gamma ray detection during the 10 μs neutron burst. BGO detectors improved the signal to background ratio for the carbon detection by a factor of six compared to 152 × 152 mm NaI (Tl) detectors. Exposure to scattered neutrons did not affect the gain stability of the BGOs. Thermal neutrons from a moderated 238PuBe source are used for the measurement of total body nitrogen (and thus protein). The resulting high energy prompt gamma rays from nitrogen (10.83 MeV) are detected simultaneously with the irradiation. BGO detectors have superior stability operating in an environment of variable neutron exposure and high counting rates. However, the presence of neutrons creates a 10.2 MeV gamma ray peak from 73Ge in the BGO detector which interferes with the nitrogen peak. Whole body gamma ray counters, consisting of NaI(Tl) crystal detectors in a shielded room, are used to measure the natural radioactivity of the body due to 40K. They are also used to measure body Ca, P, Na and Cl, following total body exposure to thermal neutrons.