David R. Chettle

Partition of circulating lead between serum and red cells is different for internal and external sources of lead

Serum lead, whole blood lead, and lead in both tibia and calcaneus were measured in each of 49 active lead workers. Serum lead correlated more strongly with both in vivo bone lead measurements than did whole blood lead. The ratio of serum lead to whole blood lead varied from 0.8% to 2.5% and showed a positive correlation with tibia, and an even stronger correlation with calcaneus lead. This implies that lead released from bone (endogenous exposure) results in a higher proportion of whole blood lead being in serum than is the case for exogenous exposure. This observation needs to be confirmed, and the relationships amongst the parameters must be studied further, particularly in former or retired lead workers. If confirmed, since at least a portion of lead in serum is readily diffusible and thus toxicologically more immediately significant than lead bound to red cells, the health implications of endogenous exposure may have to be reassessed.

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 improved instrument for the in vivo detection of lead in bone.

An improved instrument for the fluorescence excitation measurement of concentrations of lead in bone has been developed. This is based on a large area high purity germanium detector and a point source of 109Cd. The source is positioned in a tungsten shield at the centre of the detector face such that 88keV photons cannot enter the detector directly. In vivo measurements are calibrated with plaster of Paris phantoms. Occupationally non-exposed men show a minimum detectable concentration of about 6 micrograms/g bone mineral. Measurements of tibia lead concentrations in 30 non-occupationally exposed men between the ages of 23 and 73 showed an annual increment of 0.46 microgram/g bone mineral/year. The mean deviation from the regression of tibia lead upon age was 3.5 micrograms/g bone mineral. Tibia lead concentration in one subject with a history of exposure to lead was 69.6 (SD 3.5) micrograms/g bone mineral. The improved precision of the point source large detector system means that greater confidence can be placed on the results of in vivo measurements of lead concentration. This will allow studies of the natural history of non-occupational lead accumulation in normal subjects and should permit investigations of the efficacy of therapeutic interventions in subjects poisoned with lead.

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.

Further experience with bone lead content measurements in residents of southern Ontario.

Bone lead content of the mid-tibia was measured by in vivo fluorescence excitation in 90 females and 59 males aged between 6 and 81. The cross-sectionally derived rate of increase of tibia lead content was 0.24 +/- 0.03 microgram [g mineral]-1 yr-1. In 93 adult women, the corresponding rate of increase for calcaneus lead content was 0.12 +/- 0.11 microgram [g mineral]-1 yr-1. Comparison with European values show that, in Canada, the rates of lead accumulation are greater than those found in N. Sweden and Finland, similar to those of S. Sweden and less than values measured in England.

The reproducibility of 109Cd-based X-ray fluorescence measurements of bone lead.

We assessed the reproducibility of X-ray fluorescence-based lead measurements from multiple measurements made on a low-concentration plaster of paris phantom and in five subjects measured five times on two occasions. Over a 6-month period, 220 measurements of the same phantom were obtained and showed a standard deviation of 1.29 micrograms Pb (g plaster of paris)-1. The two sets of in vivo measurements were made 10 months apart and revealed a mean standard deviation of 3.4 micrograms Pb (g bone mineral)-1 and 5.1 micrograms Pb (g bone mineral)-1 for males and females, respectively. Our measured standard deviation exceeded by 20-30% the calculated standard deviation associated with a single measurement both in the phantom and in subjects. This indicates that some variance is introduced during the measurement process. Operator learning and consistency significantly minimized this increased variability. Measured lead concentrations of the left and right tibia in 14 subjects showed no significant differences between legs. As a result, either tibia can be sampled and compared over time. The levels of reproducibility we report here mean that X-ray fluorescence-based determinations of bone lead concentrations are reliable both over the short and long term. Thus, reasonably sized confidence intervals can be placed on detected changes in concentration and should permit acquisition of longitudinal data within a reasonable length of time. ImagesFigure 1.

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.