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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.

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The concentrations and isotope ratios of lead in blood and urine, on the hands, and in duplicate diet samples were measured for children living in Omaha, Nebraska. One group consisted of 22 children followed from birth to between 1 and 2 years of age and another group was 20 2- to 4-year-old children followed for 1 year, although some in each group were followed for periods between 3 and 4 years. At no time in life was a component of dietary lead identified in blood by isotope ratios, and blood lead appears dominated by lead derived from the hands, which in turn appears derived from the floors. For some homes floor lead appeared to be a mixture of lead from window sills and from the exterior. Only 2 of the children appear to have ingested lead directly from window sills. Several who lived in homes being remodeled were exposed to lead before the age of 2 years. For those who had been briefly exposed during professional remodeling the blood lead fell with a half-life of 10 months but for those who had suffered prolonged exposure during remodeling by parents the apparent half-life was longer, between 20 and 38 months.

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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.

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The observation of orthostatic hypotension in an index case of manganese toxicity lead to this prospective attempt to evaluate cardiovascular autonomic function and cognitive and emotional neurotoxicity in eight manganese alloy welders and machinists. The subjects consisted of a convenience sample consisting of an index case of manganese dementia, his four co-workers in a "frog shop" for gouging, welding, and grinding repair of high manganese railway track and a convenience sample of three mild steel welders with lesser manganese exposure also referred because of cognitive or autonomic symptoms. Frog shop air manganese samples 9.6-10 years before and 1.2-3.4 years after the diagnosis of the index case exceeded 1.0 mg/m3 in 29% and 0.2 mg/m3 in 62%. Twenty-four-hour electrocardiographic (Holter) monitoring was used to determine the temporal variability of the heartrate (RR' interval) and the rates of change at low frequency (0.04-0.15 Hz) and high frequency (0.15-0.40 Hz). MMPI and MCMI personality assessment and short-term memory, figure copy, controlled oral word association, and symbol digit tests were used. The five frog shop workers had abnormal sympathovagal balance with decreased high frequency variability (increased ln LF/ln HF). Seven of the eight workers had symptoms of autonomic dysfunction and significantly decreased heart rate variability (rMSSD) but these did not distinguish the relative exposure. Mood or affect was disturbed in all with associated changes in short-term memory and attention in four of the subjects. There were no significant correlations with serum or urine manganese. Power spectrum analysis of 24-h ambulatory ECG indicating a decrease in parasympathetic high frequency activation of heart rate variability may provide a sensitive index of central autonomic dysfunction reflecting increased exposure to manganese, although the contribution of exposures to solvents and other metals cannot be excluded. Neurotoxicity due to the gouging, welding, and grinding of mild steel and high manganese alloys (11-25%) merits air manganese and neuropsychologic surveillance including autonomic function by Holter monitoring of cardiovagal activation.

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OBJECTIVE: To determine the amount of lead ingested in food by means of duplicate diet collections, nutrient intakes, and anthropometric measurements of young children. DESIGN: Once a month for a year, data were collected from 24-hour duplicate diets, hand wipes, a dust index, and anthropometric measurements. Quarterly, venous blood samples were obtained. Thermal ionization spectrometry by means of a lead-205 tracer was used to determine lead present in food, blood, and the hand wipes. A dust index was determined on the basis of observation of dust on surfaces in the home. Anthropometric measurements obtained were height, weight, head circumference, and mid-upper arm circumference. SUBJECTS/SETTING: Subjects were 21 children, aged 18 to 36 months, who resided in homes located in an urban area with potentially high lead levels. MAIN OUTCOMES MEASURED: Lead contamination in food and on hands, and blood lead values, were determined. STATISTICAL ANALYSIS PERFORMED: Pearson correlation coefficients were used to determine relationships between lead content in food, blood, and hand wipes and growth. Multiple regression analyses examined the effect of food types and dust lead on lead levels in food, and the effect of these variables on head circumference. RESULTS: Mean blood levels were 0.3089 +/- 0.1496 micromol/L; 12 samples contained more than 0.4826 micromol/L. Total intake of lead from food was 4.95 microg/day and ranged from 1.10 to -22.10 microg/day. More than a fourth of the diets collected exceeded 6.00 microg/day. Foods considered home prepared were moderately related to blood lead level, and the dust index and hand wipe lead levels were related to total food lead. Home-handled foods, canned foods, and hand-wipe lead were significant predictors of the lead content in food. A negative relationship was found between head circumference and blood lead level. APPLICATIONS: Level of lead in food was directly related to hand-wipe lead. This finding underscores the need for dietitians and other health professionals to stress the importance of cleanliness in environments that are potentially lead contaminated. Appropriate hand washing and surface cleaning should be emphasized when preparing and consuming food. The inverse relationship between head circumference and blood lead levels points to the need for additional studies to validate this finding while controlling for other extraneous variables.

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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.

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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.

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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 mumol l-1 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 mumol l-1 lead and cytotoxicity at 20 versus 6 and over 20 mumol l-1 lead, respectively, for these variables in rat osteosarcoma cells. Both cell lines attained the highest lead concentration in the 15,000 x 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.

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From 3 million to 4 million children in America have lead poisoning. This environmental toxin affects 1 in every 6 children younger than 6 years of age in the United States. The marked effects of lead toxicity on the central nervous system are well known, ie, lowering IQ and impairing memory, reaction time, and the ability to concentrate. Children are at greatest risk for the central nervous system effects of lead because the central nervous system is at its peak in development during the first few years of life. The negative correlation of stature and blood lead level (bPb) found in the National Health and Nutrition Examination Survey directed the authors to evaluate the possible neuroendocrine effects of this toxin in children. Twelve children were studied during toxic (greater than or equal to 40 micrograms/dL) and low bPb (less than 40 micrograms/dL). Classic provocative stimuli, L-dopa (15 mg/kg by mouth) and insulin (0.1 U/kg given intravenously), were used to determine human growth hormone (hGH) responses during toxic bPb and after chelation therapy in six of the subjects. An additional four subjects were studied during low bPb. In two patients LGH levels were determined every 20 minutes for 24 hours during toxic bPb. Thyroid-stimulating hormone and prolactin responses to thyrotropin-releasing hormone were also determined. All children studied showed growth retardation during toxic bPb. Mean peak hGH responses to provocative stimuli were lower during toxic bPb, but the responses were all within normal limits.(ABSTRACT TRUNCATED AT 250 WORDS)

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ROS 17/2.8 cells, a cloned rat osteosarcoma cell line, are exceptionally sensitive to the cytotoxic effects of cadmium. This sensitivity is associated with the inability of this metal to induce the synthesis of metallothionein, a transition metal-binding protein, which detoxifies this metal by its sequestration. Sodium butyrate induces the synthesis of metallothionein in these cells in a concentration-dependent manner. Treatment with this agent also significantly increases the resistance of these cells to the cytotoxic effects of cadmium and the protective effect of butyrate is reversed upon its removal from culture medium. Butyrate treatment did not significantly alter the accumulation of cadmium by these cells. Hence, the increased synthesis of metallothionein in butyrate-treated cells is not due to increased cellular uptake of cadmium. Inhibition of DNA synthesis due to butyrate was not a sufficient condition to alter metallothionein synthesis or to protect against Cd-induced cytotoxicity. Equivalent inhibition of DNA synthesis with hydroxyurea failed to increase metallothionein synthesis in cadmium-treated cells. These results indicate that modulation of metallothionein gene expression in this cell line is the critical factor in determining cellular sensitivity to the cytotoxic effects of cadmium.

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ROS 17/2.8 cells, a cloned rat osteoblastic osteosarcoma cell line, were found to be extremely sensitive to the lethal effects of cadmium and to synthesize little, if any, metallothionein in response to cadmium exposure. Culture of cells for 24 h in the presence of 1 microM 5-azacytidine, a cytidine analog, increased the inducibility of metallothionein by cadmium and significantly reduced (P less than 0.001) cytotoxicity. Anion exchange chromatographic analysis of cadmium binding to low molecular mass cytotoxicity. Anion exchange chromatographic analysis of cadmium binding to low molecular mass cytosolic proteins showed that cells treated with cadmium and 5-azacytidine expressed at least 2 isoforms of metallothionein. One isoform of metallothionein with a low affinity for cadmium was constitutively expressed by these cells. The association of poor inducibility of metallothionein by cadmium with extreme sensitivity of cells to cadmium emphasizes the role of this protein in the cellular response to this toxic metal. The modulation of metallothionein inducibility and sensitivity to cadmium by 5-azacytidine treatment suggest that metallothionein gene structure and regulation are altered in ROS 17/2.8 cells.

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Low-level exposure to lead impairs longitudinal growth in children and in experimental animals. The proposed mechanisms include decreased osteocalcin secretion in response to 1 alpha,25-(OH)2 vitamin D3 and decreased response to insulin-like growth factor-I. The interaction of lead, 1 alpha,25-(OH)2 vitamin D3, and insulin-like growth factor-I was investigated in an osteoblast-like cell line from rat osteosarcoma, ROS 17/2.8. Cells were cultured 24 hr in a serum-free medium with lead, 1 alpha,25-(OH)2 vitamin D3, and insulin-like growth factor-I. 1 alpha,25-(OH)2 vitamin D3 (10 nM) evoked a 4-5 X increase in osteocalcin secretion and a 100% increase in cellular alkaline phosphatase activity but no increase in DNA/cell layer. Insulin-like growth factor-I (92.5 ng/ml) evoked a 100% increase of osteocalcin secretion and a 20% increase in cellular DNA contents but no change in cellular alkaline phosphatase activity. Basal and stimulated cellular osteocalcin secretion, cellular alkaline phosphatase activity, and DNA contents were significantly inhibited by addition of 1-10 microM lead. The data are consistent with a toxic effect of lead on osteoblastic function and the cellular responses to 1 alpha,25-(OH)2 vitamin D3 and insulin-like growth factor-I. This interaction may be relevant to impaired childhood growth at low levels of lead exposure.

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Inadequate vitamin D intake is an important cofactor in clinical and experimental bone disease induced by chronic cadmium exposure. The interaction was investigated by culture of rat osteoblastic osteosarcoma cells (ROS 17/2.8) in a serum-free medium with equimolar concentrations of cadmium chloride and 1 alpha,25-(OH)2 vitamin D3. After addition of cadmium alone to culture medium, the unstimulated secretion of osteocalcin and cellular alkaline phosphatase activity were inhibited at 10 pM, and of DNA synthesis and proline incorporation into collagen at 500 nM. In the presence of equimolar amounts of cadmium and 1 alpha,25-(OH)2 vitamin D3, all four responses paralleled those of 1 alpha,25-(OH)2 vitamin D3 alone up to the inhibitory concentration of 500 nM cadmium. Neither 10 nM 1 alpha,25-(OH)2 vitamin D3 nor 1 microM cadmium induced synthesis of metallothionein in these cells indicating that the protective effect of D3 was not related to the induction of a metallothionein-like protein in ROS 17/2.8 cells. In the presence or absence of D3, cadmium inhibited osteoblastic function at concentrations below the whole-organ concentration of cadmium in bone as reported in experimental and clinical cadmium-induced osteotoxicity. The extreme sensitivity of ROS 17/2.8 cells to cadmium may relate to the absence of metallothionein synthesis.

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The National Health and Nutrition Survey 1976-1980 demonstrated the inverse association of blood lead 8-35 micrograms/dl (0.4-1.7 microM) with height and weight in 2680 children 1-7 yr old. Growth has not been examined. A retrospective pilot study was made of growth, 0-42 mo, for 54 children found to have erythrocyte protoporphyrins greater than 35 micrograms/dl (0.6 mM) at 12-23 mo. For 24/54, all blood leads were less than 30 micrograms/dl (1.2 microM), with a peak annual mean of 18.5 micrograms/dl (0.9 microM); for 30/54, mean blood lead was 46.7 micrograms/dl (2.2 microM) at 12-23 mo with all subsequent blood leads greater than or equal to 30 micrograms/dl (1.2 microM). In both groups the mean height and weight at birth were at the 25th percentile. The high-lead children had increased weight velocity at 15 mo of age and were heavier at 24 mo. Weight gain related to total caloric intake, supporting food consumption, and hand-to-mouth behavior as significant factors in an increased blood lead ages 9-24 mo. The monthly directional change of height and weight percentiles after 24 mo, however, showed a decreased frequency of upward shifts when blood lead was greater than or equal to 30 micrograms/dl. Although an early high food intake appears to contribute to high blood lead by increasing the intake of lead from food and mouthing, persistent increases in the high blood lead and erythrocyte protoporphyrins were associated with subsequent growth retardation.

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