A neutron activation technique for manganese measurements in humans.

Manganese (Mn) is an essential element for humans, animals, and plants and is required for growth, development, and maintenance of health. Studies show that Mn metabolism is similar to that of iron, therefore, increased Mn levels in humans could interfere with the absorption of dietary iron leading to anemia. Also, excess exposure to Mn dust, leads to nervous system disorders similar to Parkinson's disease. Higher exposure to Mn is essentially related to industrial pollution. Thus, there is a benefit in developing a clean non-invasive technique for monitoring such increased levels of Mn in order to understand the risk of disease and development of appropriate treatments. To this end, the feasibility of Mn measurements with their minimum detection limits (MDL) has been reported earlier from the McMaster group. This work presents improvement to Mn assessment using an upgraded system and optimized times of irradiation and counting for induced gamma activity of Mn. The technique utilizes the high proton current Tandetron accelerator producing neutrons via the (7)Li(p,n)(7)Be reaction at McMaster University and an array of nine NaI (Tl) detectors in a 4 π geometry for delayed counting of gamma rays. The neutron irradiation of a set of phantoms was performed with protocols having different proton energy, current and time of irradiation. The improved MDLs estimated using the upgraded set up and constrained timings are reported as 0.67 µgMn/gCa for 2.3 MeV protons and 0.71 µgMn/gCa for 2.0 MeV protons. These are a factor of about 2.3 times better than previous measurements done at McMaster University using the in vivo set-up. Also, because of lower dose-equivalent and a relatively close MDL, the combination of: 2.0 MeV; 300 µA; 3 min protocol is recommended as compared to 2.3 MeV; 400 µA; 45 s protocol for further measurements of Mn in vivo.

Evaluation and modification of a physiologically based model of lead kinetics using data from a sequential isotope study in cynomolgus monkeys.

Endogenous (predominantly bone) and exogenous lead were differentially labeled in two 11-year-old female cynomolgus monkeys (Macaca fascicularis) to establish the contributions of the two sources to blood lead. The monkeys had been administered a common lead isotope "mix" at the rate of about 1300 micrograms Pb/kg body wt/day from age 10 months until the start of the study. On day 0, common lead was replaced in sequence by mixes artificially enriched in 204Pb, 206Pb, and 207Pb, given for periods of from 50 to 281 days. Total lead ingestion rate was held constant except during administration of the 207Pb-enriched mix to one of the monkeys, when it was reduced to 650 micrograms/kg/day. Blood and bone were sampled at intervals and analyzed for their content of each of the isotope mixes. A physiologically based model of human lead kinetics was scaled to the cynomolgus monkey and fit to the data to test the correctness of the model structure and to assist with interpretation of study results. Fractional absorption was varied to achieve the best visual fits of the scaled model to blood and bone concentration data for each monkey. The model failed to reproduce the sharp drop in isotope concentrations in blood observed after each exchange of isotope mix. Consequently, it was revised to include a rapid-turnover trabecular bone compartment and a slow-turnover cortical bone compartment, using estimates of trabecular and cortical bone turnover rates from histomorphometric studies in adult cynomolgus monkeys. The revised model fit most of the sets of bone and blood concentrations well. About 17% of the blood lead originated from bone after 11 years of exposure, at blood lead concentrations in excess of 50 micrograms/dl. The rate of return of common lead from bone, as estimated from the model, was 28 micrograms/day just before termination of controlled common lead exposure on day 0. Based on the success of the scaled human model in fitting these data and on the absolute and relative values of bone and blood lead concentrations, the metabolism of lead in the cynomolgus monkey appears to be similar to human lead metabolism.

Use of sequentially administered stable lead isotopes to investigate changes in blood lead during pregnancy in a nonhuman primate (Macaca fascicularis).

The effects of pregnancy on the flux of lead from maternal bone were investigated in five females from a unique colony of cynomolgus monkeys (Macaca fascicularis) which had been dosed orally with lead (approximately 1100-1300 microg Pb/kg body wt) throughout their lives (about 14 years). Through the use of stable lead isotopes 204Pb, 206Pb, and 207Pb, it was possible to differentiate between the lead contributed to blood lead from the skeleton and the lead contributed from the current oral dose. Blood samples and bone biopsy samples taken before, during, and after pregnancy were analyzed for lead (total and stable isotope ratios) by thermal ionization mass spectrometry. Through the use of end-member unmixing equations, the contribution to blood of lead from maternal bone during pregnancy was estimated and compared to the contribution of lead from maternal bone before pregnancy. A 29 to 56% decrease in bone lead mobilization in the first trimester was followed by an increase in the second and third trimesters, up to 44% over baseline levels. In one monkey, the third-trimester increase did not reach baseline levels. In a single low-lead monkey, a similar decrease in the first trimester was followed by a 60% increase in the third trimester, indicating that a similar pattern of flux is seen over a wide range of lead concentrations. Analysis of maternal bone and fetal bone, brain, liver, and kidneys confirmed a substantial transplacental transfer of endogenous lead. Lead concentrations in fetal bone often exceeded maternal bone lead concentrations. From 7 to 39% of the lead in the fetal skeleton originated from the maternal skeleton.

Measurement of the flux of lead from bone to blood in a nonhuman primate (Macaca fascicularis) by sequential administration of stable lead isotopes.

To better understand the kinetics of the transfer of lead from bone to blood, we have developed and tested a method in which sequential doses of lead, each enriched with a different stable isotope, were administered in a nonhuman primate Macaca fascicularis whose skeleton had been previously labeled with lead of known isotopic composition. Lead isotopic ratios of blood and bone samples, analyzed by thermal ionization mass spectrometry (TIMS), were unmixed by isotope dilution techniques. The first label administered allows the contribution from historical bone stores to be measured. Subsequent labels allow measurement of both the historical bone stores and the previous labels that have become recently incorporated into bone. The method may be extended to studies of bone lead mobilization in pregnancy, lactation, menopause, or in disease states such as postmenopausal osteoporosis.

Plasma and blood lead concentrations, lead absorption, and lead excretion in nonhuman primates.

In order to assess the comparability of lead disposition in the cynomolgus monkey to that in the human, we determined the relationships among blood lead concentration, plasma lead concentration, and lead excretion in monkeys. Six adult (3-5 kg) female cynomolgus monkeys (Macaca fascicularis) without previous experimental lead exposure were given single intravenous injections of from 750 to 3300 micrograms lead as lead nitrate, labeled with 210Pb, per kilogram body weight. Four additional monkeys, fasted overnight, were administered single oral doses of either 750 or 1500 micrograms lead as lead nitrate, labeled with 210 Pb, per kilogram for the assessment of fractional absorption. Blood and plasma lead concentrations (10 monkeys) and urinary and fecal excretion of lead (2 monkeys) were followed up for up to 16 days after lead administration. Fractional absorption from an oral dose was 44% at the lower of the two doses and 22-28% at the higher dose. The relationship between plasma and blood lead concentrations was found to be similar to that in humans, with plasma lead concentration at most a few percent of total blood lead concentration at low concentrations. Partitioning of lead across the red cell membrane in the 2 monkeys given exceptionally high doses (3300 micrograms/kg) intravenously was distinctly lower than that in the 4 monkeys given lower intravenous doses. Urinary clearance of lead in these 2 monkeys was 19% of the estimated glomerular filtration rate, within the range of efficiencies reported for humans. Fecal clearance, however, was anomalous and appeared to be an artifact of the very high dose. Examination of published data for urinary and fecal lead excretion in three adult baboons showed that both functions in the baboons were quantitatively similar to those in humans. Urinary clearance in the baboons was 14-24% of the estimated glomerular filtration rate, and fecal clearance was 78-85% of the urinary clearance. We conclude that nonhuman and human primates are comparable with respect to the relationship of plasma lead concentration to blood lead concentration and the relative efficiency of lead excretion in urine and feces.

Sampling of cortical and trabecular bone for lead analysis: method development in a study of lead mobilization during pregnancy.

The paper describes a methodological approach to the investigation of maternal-fetal transfer of lead in a non-human primate species, with particular focus on skeletal tissue, which is known to be a site of lead deposition. Eight female cynomolgus monkeys were dosed with lead acetate during gestation, and in four of the animals, the isotopic composition of the lead was modified by enriching the amount of the stable isotope 204Pb included in the dose. Biopsy and dissection procedures for the preparation of bone samples for lead analysis and stable lead isotope analysis are described. Emphasis is placed on the containment of potential contamination of the samples by lead during preparation. Containment procedures included: use of a Class 100 clean room, special cleaning regimes and use of Teflon containers and stainless steel instruments. Preliminary data of lead concentrations in adult bone (trabecular and cortical) and fetal bone subsequent to the dosing regimen of lead during pregnancy, suggest notable differences between the two bone "compartments" examined. The bone samples of fetuses from the dams which had received enriched 204Pb showed drastically reduced 206Pb/204Pb isotope ratios.

The significance of anti-C sensitization in pregnancy.

A study of maternal blood samples from 280,000 pregnancies in an 8-year period has shown 38 examples of anti-C (without anti-D) sensitization. This frequency (0.14/1000 pregnancies) was lower than that previously found for anti-c (0.63/1000 pregnancies) and for anti-D (2.55/1000 pregnancies). Although most of the 38 babies born to mothers with anti-C were unaffected by haemolytic disease of the newborn and none was anaemic at birth, two required exchange transfusion for hyperbilirubinaemia and one a top-up transfusion. Five cord blood samples had a positive direct antiglobulin test.

Pre-transfusion non-invasive quality assessment of stored platelet concentrates.

The Platelet Monitor System has been designed to assess routinely prepared platelet concentrates (P.C.) during storage. The system is based upon observations of changes in light transmission induced by platelets in intact packs. It is practical, provides constant gentle agitation for P.C., and non-invasively give continuous semi-quantitative evidence of the probable numbers of discoid platelets within each pack. The information yielded correlates both with established in vitro parameters of platelet behaviour, and with in vivo survival of platelets in normal healthy volunteers. The device safely provides the Blood Banker with the means to achieve on-going assessment of methods and improvements--or failings--in P.C. production. To the clinician it offers information throughout and even beyond present arbitrary storage limits, about which P.C. are likely to be of least or greatest value to a thrombocytopenic patient.

Lead-based paint in dwellings: The potential for contamination of the home environment during renovation.

The quantity and particle size characteristics of lead in dust released during three different paint removal techniques was determined under controlled conditions and in situ in a dwelling. Air-lead and deposited dust-lead levels were highest after sanding but 'burning-off' and 'hot-air' removal methods also produced significant contamination. The importance of dust particle-size and lead is discussed in relation to the potential hazard to home renovators via inhalation and to children via the 'hand-to-mouth' route.

The significance of anti-c alloimmunization in pregnancy.

In an 8-year period, 177 of 280,000 pregnancies were complicated by maternal anti-c alloimmunization. Although there was one neonatal death associated with anti-c haemolytic disease of the newborn, only two infants were severely anaemic at birth. A total of 11 babies required exchange transfusion, but nine of these developed hyperbilirubinaemia alone. The remaining c positive infants were either unaffected or only mildly affected by erythroblastosis fetalis. A strategy for management of these pregnancies is outlined, and proposed methods of prevention and serological control are discussed.

Lead in playground dust and on the hands of schoolchildren.

Measurements of the quantity of lead on the hands of schoolchildren and of the concentration of lead in dust from school playgrounds have been carried out; the hand-lead was collected by wiping with a moist tissue. When hand-lead and dust-lead values were averaged for each school, a statistically significant relationship between the two sets of means was obtained. Some limited measurements of size distribution of the dust particles on the children's wipes were also made; these indicated that most of the particles were less than 10 micron in diameter.

Review of the health effects of methylmercury.

The study critically reviews recent data relating to the health effects of methylmercury in man and the attendant dose-response relationships. New data obtained from animal studies, including pre-and postnatal exposure, are also examined. The consumption of fish and fish produce represents the major source of methylmercury exposure in the general population. Reported mercury concentrations in fish throughout the world are examined, particularly in the Mediterranean Sea. Here there is limited knowledge of methylmercury intake in critically exposed populations such as fishermen, employees of the fish industries and their families. The measurement of mercury in hair is now regarded as the most useful indicator of exposure but more experimental data are still required to increase the value of this index. The threshold levels of methylmercury in blood, hair and for dietary intake, as estimated by the World Health Organization, have been largely endorsed. However, new information from Japan and Canada suggests the existence of a latency period for some effects, so that the frequency or probability of their occurrence is inversely related to the duration of exposure. Incorporation of such findings would therefore lead to the designation of lower threshold values than are presently recognized. Pregnant women and the fetus have been identified as groups that are at special risk. The fetal blood mercury level is up to twice that of the mother and the sensitivity of both mother and fetus may be higher than in non-pregnant adults. This should be taken into account when assigning protective threshold concentrations.