Fiona E. McNeill

A Dose Threshold for a Medium Transfer Bystander Effect for a Human Skin Cell Line

Abstract Liu, Z., Mothersill, C. E., McNeill, F. E., Lyng, F. M., Byun, S. H., Seymour, C. B. and Prestwich, W. V. A Dose Threshold for a Medium Transfer Bystander Effect for a Human Skin Cell Line. Radiat. Res. 166, 19–23 (2006). The existence of radiation-induced bystander effects mediated by diffusible factors is now accepted, but the mechanisms and precise behavior at low doses remain unclear. We exposed cells to γ-ray doses in the range 0.04 mGy–5 Gy, harvested the culture medium, and transferred it to unirradiated reporter cells. Calcium fluxes and clonogenic survival were measured in the recipients. We show evidence for a dose threshold around 2 mGy for the human skin cell line used with a suggestion of increased survival below that dose. Similar experiments using direct γ irradiation showed no reduction in survival until the dose exceeded 7 mGy. Preliminary data for neutrons where the γ-ray dose was kept below the bystander threshold do not show a significant bystander effect in the dose range 1–33 mGy. A lack of a bystander response with neutrons occurred at around 1 Gy, where significant cell killing from direct irradiation was observed. The result may have implications for understanding the role of bystander effects at low doses.

Neurotoxicity in young adults 20 years after childhood exposure to lead: the Bunker Hill experience

OBJECTIVES: An epidemiological study of young adults was conducted to determine whether environmental exposure to lead during childhood was associated with current adverse neurobehavioural effects. METHODS: The exposed group consisted of 281 young adults who had been exposed environmentally to lead as children and the unexposed referent group consisted of 287 age and sex frequency matched subjects. Information on demographics, past and current health, and past exposures to neurotoxicants, and responses to the Swedish Q16 questionnaire were collected by interview. Standard neurobehavioural and neurophysiological tests were administered by computer or trained technicians. K x ray fluorescence was used to estimate tibial bone lead concentrations among the exposed and unexposed groups. Associations were examined between the exposed group and referents and tibial bone lead concentration and the neurobehavioural and neurophysiological outcomes of interest. RESULTS: Among the measures of peripheral nerve function, after controlling for confounders, sural sensory nerve evoked response amplitude, peroneal motor nerve compound motor action potential amplitude, vibrotactile thresholds of fingers and toes, and standing steadiness were significantly associated with exposure group. Among the neurobehavioural tests, hand-eye coordination, simple reaction time latency, trails B latency, symbol digit latency, serial digit, and learning error score were also significantly associated with exposure group after controlling for confounders. Exposed subjects had significantly more neuropsychiatric symptoms than the referents. Associations between tibial bone lead concentration and scores for vocabulary, vibrotactile thresholds of the fingers, and vibrotactile thresholds of the toes approached significance. CONCLUSIONS: Significant adverse central and peripheral neurological effects were found in a group of young adults 20 years after childhood environmental exposure to lead when compared with non-exposed controls. The absence of a significant association between neurological outcomes and tibial bone lead concentration, and the presence of significant associations between neurological outcomes and exposure group may be due to either the magnitude of measurement uncertainty in K x ray films relative to the actual tibial bone lead concentration in these young non-occupationally exposed subjects, or uncontrolled confounding of the exposure group.

Impact of occupational exposure on lead levels in women.

In 1994, 207 women participated in a study designed to examine the effects of occupational exposure and various lifestyle factors on bone and blood lead levels. In vivo measurements of Pb concentrations in tibia were performed by X-ray fluorescence. All 108 former smelter employees and 99 referents provided blood samples and answered a questionnaire on lifestyle characteristics and the relevant medical history. Lead concentrations in tibia and blood were significantly higher in the exposed group. The difference in mean bone Pb concentrations of the two groups is markedly greater than the difference in the mean blood Pb concentrations, supporting the view that bone Pb measurements are a more reliable determinant of Pb body burden. Chronic exposure did not result in any statistically significant differences in adverse pregnancy outcomes. A significantly lower age at the onset of menopause in occupationally exposed women may suggest that Pb causes adverse changes in the pattern of estrus and menses. The exposed women had lower bone Pb concentrations than those found in most studies on predominantly male workers. Blood Pb concentrations remain increased in women long after the cessation of occupational exposure, reflecting the importance of the endogenous exposure. The endogenous exposure relation found for postmenopausal exposed women is consistent with data on male smelter workers, whereas the relation found for premenopausal women is significantly lower. This suggests that sex plays an important role in the metabolism of lead, and current models of exposure extrapolated from male data may be inappropriate for use on women.

In vivo X-ray fluorescence of lead in bone using K X-ray excitation with 109Cd sources : radiation dosimetry studies

Independent experiments have been performed at two centers, to evaluate the dosimetric properties of their respective 109Cd K X-ray fluorescence (XRF) bone lead measurement systems. Measurements were made of the dose to several points on the skin on the lower leg, at the surface of the tibia, in the red marrow tibia cavity, at the midcalf, and in the abdominal region occupied by the conceptus. Overall agreement between the two data sets was found. Similarities and differences are discussed. The effective dose values for an in vivo measurement of tibia lead concentration in 1-, 5-, and 10-year-old and adult subjects were calculated from one data set to be 1100, 420, 190, and 34/38 (male/female) nSv, respectively, for an in vivo median precision (one standard deviation) of 4.9 micrograms Pb (g bone mineral)-1 for a 30-min adult measurement.

An investigation of the toxicity of gadolinium based MRI contrast agents using neutron activation analysis

The toxicity of gadolinium (Gd) based MRI contrast agents, is based upon the amount of Gd that dissociates from its chelate and deposits in tissues. In this study, the toxicities of two contrast agents were tested using different injection strategies in two animal models. Following a bolus injection of 0.2 mmol/kg of Gd-DTPA in a pilot study with a single canine, Gd levels were as high as 2.05 +/- 0.17 ppm and 0.47 +/- 0.11 ppm 2 weeks post injection in the kidney and liver tissues, respectively. To evaluate the role that the injection strategy plays in toxicity, 0.8 mmol/kg of Gd-(HP-DO3A) was injected into rats, in a second study, via bolus and constant infusion techniques. Gd was only detected in the kidney in the bolus injected rats but in the lung as well in the constant infusion injected rats. Concentrations detected in the kidney for both strategies, were comparable within error: 1.37 +/- 0.46 ppm for the bolus and 1.24 +/- 0.39 ppm for the bolus/constant infusion strategy and 0.16 +/- 0.14 ppm in the lung for the constant infusion technique. The contrast infusion technique does not appear to present an increased risk of toxicity over the bolus technique except perhaps to a small degree in the lung.

In vivo X-ray fluorescence of lead in bone.

The in vivo measurement of lead in bone by K X-ray fluorescence (K XRF) is becoming an increasingly widely utilized technique for assessing long-term lead dosimetry. Several groups have already reported the development of in vivo measurement systems, the majority adopting the 109Cd/backscatter K XRF technique because of its substantial advantages in terms of a robust measurement, lower detection limit (compared with 57Co/90 degrees), absence of the need for sedation of younger subjects, and lower effective (radiation) dose when calculated according to the most recent guidelines. The advantages of the 109Cd system are primarily a consequence of the physics principles of the technique. The apparatus of each XRF technique is transportable, facilitating easy establishment of mobile laboratory facilities. More research is needed to substantiate claims made for particular XRF technologies, but both L and K XRF techniques provide the possibility of improved understanding of the bodys handling of the ubiquitous toxin lead.

Dosimetric characterization of the irradiation cavity for accelerator-based in vivo neutron activation analysis

A neutron irradiation cavity for in vivo activation analysis has been characterized to estimate its dosimetric specifications. The cavity is defined to confine irradiation to the hand and modifies the neutron spectrum produced by a low energy accelerator neutron source to optimize activation per dose. Neutron and gamma-ray dose rates were measured with the microdosimetric technique using a tissue-equivalent proportional counter at the hand irradiation site and inside the hand access hole. For the outside of the cavity, a spherical neutron dose equivalent meter and a Farmer dosemeter were employed instead due to the low intensity of the radiation field. The maximum dose equivalent rate at the outside of the cavity was 2.94 microSv/100 microA min, which is lower by a factor of 1/2260 than the dose rate at the hand irradiation position. The local dose contributions from a hand, an arm and the rest of a body to the effective dose rate were estimated to be 1.73, 0.782 and 2.94 microSv/100 microA min, respectively. For the standard irradiation protocol of the in vivo hand activation, 300 microA min, an effective dose of 16.3 microSv would be delivered.

Grid search: an innovative method for the estimation of the rates of lead exchange between body compartments

This paper describes a new metabolic model for lead in humans and a numerical method to solve the differential equations governing the transfer of lead between body compartments. The model includes 3 compartments-cortical bone, trabecular bone and blood-and accounts for absorption from external sources and release through excreta. Estimation of the lead kinetics parameters was performed using the grid search method. Grid search is a simple procedure that allows the fit of an arbitrary function to data. When applied to data from occupationally exposed populations, the method demonstrated the exposure dependence of the rate of lead uptake and release by the compartments in the model. The results confirm and refine previous observations of the significant decrease of the transfer rate of lead from cortical bone to blood with increasing exposure, as expressed by half-lives of (in years): 6.5 +/- 0.7, 13.6 +/- 1.0 and 47.5 +/- 2.3, in subgroups of low, intermediate and high long-term lead exposure. A similar trend was observed for the transfer rate from trabecular bone, which could be statistically supported for the first time. Reduction by a factor of 7 to 10 in the default values assigned to the fractional removal of lead from cortical bone to plasma in existing metabolic models was also predicted. These results can be used in the review of current metabolic models for lead, which are still based on the assumption of a constant rate of lead removal from bone, independently of the level of exposure.

In Vivo Measurements of Lead in Bone Using a 109Cd ‘SPOT’ Source

The principles of X-ray fluorescence (XRF) have been described elsewhere1. The XRF technique described here uses the 88.035 keV γ-rays from 109Cd which fluoresce the K shell X-rays of lead and a backscatter geometry is adopted. This technique was developed at the University of Birmingham, England2. In addition to the one described here, further measurement systems are under development3.

An accelerator based system for in vivo neutron activation analysis measurements of manganese in human hand bones

Manganese (Mn) is an essential nutrient for growth and development. Unfortunately, overexposure can lead to neurological damage, which is manifested as a movement disorder marked by tremors. Preclinical symptoms have been found in populations occupationally exposed to the element, and it is suggested that in late stages of the disorder, removing the Mn exposure will not prevent symptoms from progressing. Hence, it is desirable to have a means of monitoring Mn body burden. In vivo neutron activation analysis (IVNAA) is a technique which allows the concentration of some elements to be determined within sites of the body without invasive procedures. Data in the literature suggests that the Mn concentration in bone is greater than other tissues, and that it may be a long term storage site following exposure. Therefore, using the McMaster KN-accelerator to produce neutrons through the 7Li(p,n)7Be reaction, the feasibility of IVNAA for measuring Mn levels in the human hand bone was investigated. Mn is activated through the 55Mn(n,gamma)56Mn reaction, and the 847 keV gamma rays emitted when 56Mn decays are measured outside the body using NaI(Tl) detectors. An optimal incident proton energy of 2.00 MeV was determined from indium foil and microdosimetry measurements. Hand phantom data suggest a minimum detectable limit of approximately 1.8 ppm could be achieved with a reasonably low dose of 50 mSv to the hand (normal manganese levels in the human hand are approximately 1 ppm). It is recommended the technique be developed further to make human in vivo measurements.