Carol R. Angle

Manganese encephalopathy: utility of early magnetic resonance imaging.

The use of magnetic resonance imaging (MRI) provides visual evidence of cerebral deposits of paramagnetic metals. The usefulness of MRI is described in connection with the manganese poisoning of a 44 year old arc welder who had been engaged in the repair and recycling of railroad track made of manganese steel alloy.

Release of lead from bone in pregnancy and lactation

Concentrations and isotope ratios of lead in blood, urine, 24-h duplicate diets, and hand wipes were measured for 12 women from the second trimester of pregnancy until at least 8 months after delivery. Six bottle fed and six breast fed their infants. One bottle feeder fell pregnant for a second time, as did a breast feeder, and each was followed semicontinuously for totals of 44 and 54 months, respectively. Bone resorption rather than dietary absorption controls changes in blood lead, but in pregnancy the resorption of trabecular and cortical bone are decoupled. In early pregnancy, only trabecular bone (presumably of low lead content) is resorbed, causing blood leads to fall more than expected from hemodilution alone. In late pregnancy, the sites of resorption move to cortical bone of higher lead content and blood leads rise. In bottle feeders, the cortical bone contribution ceases immediately after delivery, but any tendency for blood leads to fall may be compensated by the effect of hemoconcentration produced by the postpartum loss of plasma volume. In lactation, the whole skeleton undergoes resorption and the blood leads of nursing mothers continue to rise, reaching a maximum 6-8 months after delivery. Blood leads fall from pregnancy to pregnancy, implying that the greatest risk of lead toxicity lies with first pregnancies.

Randomized Placebo-Controlled Trial of 2,3-Dimercaptosuccinic Acid in Therapy of Chronic Arsenicosis Due to Drinking Arsenic-Contaminated Subsoil Water

INTRODUCTION Chronic arsenic toxicity producing various clinical manifestations is currently epidemic in West Bengal, India, Bangladesh, and other regions of the world. Animal studies have indicated that 2,3-dimercaptosuccinic acid can be used as an oral chelating agent. A prospective, double-blind, randomized controlled trial was carried out to evaluate the efficacy and safety of 2,3-dimercaptosuccinic acid for chronic arsenicosis due to drinking arsenic-contaminated (> or = 50 micrograms/L) subsoil water in West Bengal. METHOD Twenty-one consecutive patients with chronic arsenicosis were individually randomized (random number; assignment made by individual not evaluating patients) into 2 groups: 11 patients (10 male, age 25.5 +/- 8 years) received 2,3-dimercaptosuccinic acid 1400 mg/d (1000 mg/m2) in the first week and 1050 mg/d (750 mg/m2) during the next 2 weeks with a repeat course 3 weeks later. The other 10 patients (all male, age 32.2 +/- 9.7 years) were given placebo capsules for the same schedule. The clinical features were evaluated by an objective scoring system before and after treatment. Routine investigations including liver function tests, arsenic concentrations in urine, hair, and nails, and skin biopsy evaluations were also completed. RESULTS Though there was improvement in the clinical score of 2,3-dimercaptosuccinic acid-treated patients, similar improvement was observed in the placebo-treated group. There were no statistical differences in the clinical scores between the 2 groups at the beginning and at the end of treatment. Similarly, no differences were found for the other investigated parameters. CONCLUSION Under the conditions of this study, 2,3-dimercaptosuccinic acid was not effective in producing any clinical or biochemical benefit or any histopathological improvement of skin lesions in patients with chronic arsenicosis.

Environmental lead and children: The Omaha study

Blood lead (Pb B) was determined in 1232 samples from 831 children in Omaha and correlated with air lead (Pb A) concentrations of 0.02-1.69 microgram/m3 from 1971 to 1977. A bivariate equation for ages 6-18 yr based on these data predicts an increase in Pb B of 1.4 microgram/dl as Pb A increases from 1 to 2 microgram/m3. Pb B increases 7 microgram/dl as the mean values for soil and house dust Pb increase from 100 to 750 microgram/g. Multiple regression analysis shows that the combined effects of air, soil, and house dust Pb account for 21% of the variance of Pb B, with a high intercorrelation of all 3 variables. Since the variance of repeat sampling in individuals accounted for 38% of the total variance of Pb B, approximately 40% is unexplained and requires measurement of Pb from dietary and other sources.

Omaha childhood blood lead and environmental lead: A linear total exposure model☆

The majority of experimental and population studies of blood lead (PbB) and environmental lead, including the Omaha study, have utilized the Goldsmith-Hexter log-log or power function model. Comparison was made of the log-log model and a linear model of total exposure to describe the Omaha Study of 1074 PbBs from children ages 1-18 years as related to air (PbA), soil (PbS), and housedust (PbHD) lead. The data fit of the linear model was statistically equivalent to the power model and the predicted curves were biologically more plausible. The linear model avoids the mathematical limitations of the power model which predicts PbB zero at PbA zero. From the Omaha data, this model, ln PbB = ln (beta 0 + B1 PbA + B2 PbS + beta 3 PbHD) predicts that PbB increases 1.92 micrograms/dl as PbA increases 1.0 microgram/m3. Since PbS and PbHD increase with PbA, however, the increases in total exposure predict a PbB increase of 4-5 micrograms/dl as PbA increases 1.0 microgram/m3.

Air lead: relation to lead in blood of black school children deficient in glucose-6-phosphate dehydrogenase.

Forty-four black children at two elementary schools within 0.7 mile of a battery plant had significantly higher (P < .001) concentrations of lead in their bloods (34.1 � 9.7, micrograms per 100 milliliters, mean � standard deviation) than 122 students (26.3 � 7.1) at seven schools 1 to 3 miles distant; 5 months later there was a comparable difference between red cell lead values (54.1 � 18.5 versus 37.4 � 12.6). Among the blacks, those deficient in glucose-6-phosphate dehydro-genase had a higher (P < .005) concentration of lead in the blood after correction for anemia (32.9 � 9.7) than the nondeficient (25.7 � 8.8), and a higher concentration in the red cells (47.3 � 14.7 as compared to 35.6 � 15.8, P < .001); the enzyme effect was independent of geographic location.

Stable isotope identification of lead sources in preschool children--the Omaha Study.

The objective was to determine, from analysis of the naturally occurring stable isotopes of lead, the relative contribution of food, handdust, housedust, soil and air lead to the absorbed (urinary) lead and the blood lead of children living in a former smelter city. A longitudinal 12 month study was conducted of 21 children, 2 - 3 years of age, living in central Omaha, balanced for race, gender and socioeconomic status. Field clean samples were collected monthly of 24 hour duplicate diet, handwipe and urine, with quarterly blood lead, annual environmental lead, weekly air for total lead and 206Pb, 207Pb and 208Pb by thermal ionization/mass spectrometry with a 205Pb spike in a Class II laboratory. Despite residence in a smelter city each child had a unique isotopic ratio of handwipe, blood and urine lead, the latter being identical. There was no correlation of handwipe isotopic ratio with proximity to a lead emission source or to the decade of the housing stock. The isotopic ratio of the annual mean handwipe lead predicted 43% of the variance of the annual mean blood and urine lead ratio (r2 = .43; p = .001). Handwipe lead ratios correlated (p < or = .05) with those of the windowsills and air ducts. The mean isotopic ratios of blood and urine lead were lower than those of handwipe and food, consistent with a contribution by endogenous bone lead. Clean catch urine provides a noninvasive index of blood lead isotopic ratio in children, as in adults.

Childhood lead toxicity and impaired release of thyrotropin-stimulating hormone.

Decreased stature of children is epidemiologically associated with increased blood lead independent of multiple socioeconomic and nutritional variables. Since endocrine dysfunction occurs in adult lead workers, we studied two girls, 2 years of age, before and after calcium disodium edetate chelation for blood leads (PbB) of 19-72 micrograms/dl. The height of both children had crossed from the 50th to below the 10th percentile during the course of chronic lead toxicity. Basal free T4, T4, T3, cortisol, somatomedin C, and sex steroids were normal. A decrease in the growth hormone response and elevation of basal prolactin and gonadotropins were noted in one. Both children demonstrated blunted thyrotropin-stimulating hormone (TSH) responses to thyrotropin-releasing hormone (TRH) in six of seven challenges. This prompted in vitro studies of cultured cells from rat pituitaries. After incubation of pituitary cells with 0.1-10 microM Pb2+ for 2 hr, followed by the addition of TRH, there was a dose-dependent inhibition of TSH release. Lead did not interfere with the assay of TSH. To investigate the interaction of lead and calcium, 45Ca2+ kinetic analyses were done on rat pituitary slices after 1 hr incubation with 1.0 microM lead. The impaired late efflux was consistent with a decrease in the size and exchangeability of the tightly bound pool of intracellular microsomal or mitochondrial calcium. The rat pituitary cell model provides a model for the decreased TSH release of lead poisoning, supports the biological plausibility of a neuroendocrine effect on growth, and suggests that interference with calcium-mediated intracellular responses is a basic mechanism of lead toxicity.

Osteotoxicity of cadmium and lead in HOS TE 85 and ROS 17/2.8 cells: relation to metallothionein induction and mitochondrial binding.

Epidemiological, experimental and clinical data indicate that cadmium and lead are osteotoxins in man and other species. The relative sensitivities of a clonal human osteosarcoma cell line (HOS TE 85) and a clonal rat osteosarcoma cell line (ROS 17.28) to the cytotoxic effects of cadmium and lead were tested in serum-free media without added growth factors. The rat osteosarcoma cells were more sensitive to cadmium with cytotoxicity and inhibition of proliferation at 0.25 versus 0.75 and 1.0 μmol l− cadmium, respectively, for human osteosarcoma cell lines. The lower sensitivity to cadmium of human osteosarcoma cells is attributed, at least partly, to induction of metallothionein synthesis by cadmium and zinc in this cell line; in the rat osteosarcoma cell line, they do not induce metallothionein synthesis. Human osteosarcoma cells were more sensitive than rat osteosarcoma cells to lead with inhibition (IC50) of proliferation at 4 μmol l− lead and cytotoxicity at 20 versus 6 and over 20 μmoll− lead, respectively, for these variables in rat osteosarcoma cells. Both cells lines attained the highest lead concentration in the 15 000 × g (mitochondrial) fraction. The lead in the mitochondrial, microsomal, nuclear and cytosolic fractions of the human cell line did not decrease during 24 h post-washout. Binding of lead was much less stable in the less sensitive rat cells, with 50–100% loss of mitochondrial, microsomal and nuclear lead during 24 h post-washout.

Erythrocyte Nucleotides in Children—Increased Blood Lead and Cytidine Triphosphate

Summary: The erythrocyte nucleotides of 25 children, 1–5 years old, with normal and increased blood leads, were assayed by anion-exchange high-performance liquid chromatography. Red blood cells of the 12 children with blood lead (PbB) below 30 μ/dl (20.3 ± 6 μ/dl, X ± S.D.) had normal levels of activity of pyrimidine 5‘-nucleotidase (P5N) and their erythrocytes were virtually free of pyrimidine nucleotides except for small amounts of UMP and UDP. The purine nucleotides, predominantly ATP and GTP, were present at values similar to adults. In the 13 children with PbB 30–72 μ/dl (45.3 ± 14.3 μ/dl), total cytidine phosphates (CMP, CDP, CTP) were significantly (P < 0.001) increased from trace values to 8.31 ± 6.21 nmoles/1010 erythrocytes. The purine nucleotides were unchanged. P5N activity was 143.3 ± 22.0 units/g hemoglobin in children with PbB < 30 μ/dl and 75.4 ± 24.2 units (P < 0.001) in the high lead subjects. There was a logarithmic correlation of erythrocyte cytidine phosphates with PbB (r = 0.89, P < 0.001) and an inverse correlation of cytidine phosphates with ln P5N activity (r = 0.59, P < 0.001), of ln P5N with PbB (r = 0.64, P < 0.001) and of ln P5N with ln erythrocyte zinc protoporphyrin (Protoporphyrin IX) (r = 0.57, P < 0.001).Speculation: The accumulation of small amounts of erythrocyte CTP in children with increased lead exposure but with blood concentrations of leads as low as 30 μg/dl supports a lower threshold for the consequences of lead induced inhibition of pyrimidine 5′-nucleotidase (P5N) than indicated by earlier, less sensitive assays of nucleotides in adults with lead poisoning. The presence of CTP as the predominant pyrimidine nucleotide is similar to the profile in congenital deficiency of P5N but the nucleotides accumulate with less suppression of P5N than found in congenital deficiency. The significance of increased red cell cytidine phosphates at low levels of lead exposure is unknown but it appears to relate to suppression of P5N activity early in red cell maturation, and thus provides an index of antecedant lead exposure that correlates with erythrocyte zinc protoporphyrin.