Hyperproduction of erythropoietin in nonanemic lead-exposed children.

Lead (Pb) poisoning has numerous effects on the erythropoietic system, but the precise mechanism whereby high dose exposure causes anemia is not entirely clear. We previously reported that Pb exposure is associated with depressed serum erythropoietin (EPO) in pregnant women residing in a Pb mining town and in a nonexposed town in Kosovo, Yugoslavia. In a prospective study, we tested the hypothesis that blood Pb concentration (BPb) may be associated with depressed EPO in children. BPb, hemoglobin (Hgb), and serum EPO were measured at ages 4.5, 6.5, and 9.5 years in 211, 178, and 234 children, respectively. At 4.5 years of age, mean BPbs were 38.9 and 9.0 microg/dl in the exposed and nonexposed towns, respectively; BPbs gradually declined to 28.2 and 6.5 microg/dl, respectively, by age 9.5 years. No differences were found in Hgb at any age. At age 4. 5 years, a positive association between BPb and EPO (beta = 0.21; p = 0.0001), controlled for Hgb, was found. The magnitude of this association declined to 0.11 at age 6.5 years (p = 0.0103) and 0.03 at age 9.5 years (p = 0.39). These results were confirmed using repeated measures analyses. We concluded that in Pb-exposed children, the maintenance of normal Hgb requires hyperproduction of EPO. With advancing age (and continuing exposure), this compensatory mechanism appears to be failing, suggesting a gradual loss of renal endocrine function due to Pb exposure.

Determinants of elevated blood lead during pregnancy in a population surrounding a lead smelter in Kosovo, Yugoslavia.

We are prospectively examining the relation between environmental lead exposure and pregnancy outcome in cohorts of women exposed to a wide range of air lead concentrations. Titova Mitrovica, Yugoslavia, is the site of a large lead smelter, refinery, and battery factory. At midpregnancy, 602 women in T. Mitrovica and 900 women in Pristina, a non-lead-exposed control town, were interviewed. Blood was obtained for blood lead (PbB), hemoglobin, erythrocyte protoporphyrin, and serum ferritin measurements. Women were seen again at delivery, at which time maternal and umbilical cord blood samples were obtained. While many demographic and social characteristics were similar across the two towns, women in Pristina were more likely to report employment outside the home, cigarette smoking, and alcohol use during pregnancy. As expected, PbB levels were substantially higher in the smelter town. At midpregnancy, PbB geometric means were 17.1 micrograms/dL in T. Mitrovica and 5.1 micrograms/dL in Pristina; 86% of the pregnant women in T. Mitrovica, compared to 3.4% of those in Pristina, had PbB levels greater than 10 micrograms/dL. Within T. Mitrovica, distance between the home and the smelter was the most important predictor of PbB at mid-pregnancy and delivery. Husband's employment in the lead industry was associated with a significant increase in maternal PbB levels independent of place of residence. Higher maternal serum ferritin concentrations were associated with lower PbB levels, suggesting that dietary iron inhibits lead absorption. Overall, the placenta was a poor barrier to lead; the relationship between maternal PbB and umbilical cord PbB was linear across a wide range of PbB levels.

Lead exposure and intelligence in 7-year-old children: the Yugoslavia Prospective Study.

For a prospective study of lead exposure and early development, we recruited pregnant women from a lead smelter town and from an unexposed town in Yugoslavia and followed their children through 7 years of age. In this paper we consider associations between lifetime lead exposure, estimated by the area under the blood lead (BPb) versus time curve (AUC7), and intelligence, with particular concern for identifying lead's behavioral signature. The Wechsler Intelligence Scales for Children-Version III (WISC-III) was administered to 309 7-year-old children, 261 of whom had complete data on intelligence, blood lead, and relevant sociodemographic covariates (i.e., Home Observation for the Measurement of the Environment (HOME), birth weight, gender, sibship size, and maternal age, ethnicity, intelligence, and education). These showed anticipated associations with 7-year intelligence, explaining 41-4% of the variance in Full Scale, Performance, and Verbal IQ. Before covariate adjustment, AUC7 was unrelated to intelligence; after adjustment, AUC7 explained a significant 2.8%-4.2% of the variance in IQ. After adjustment, a change in lifetime BPb from 10 to 30 micro/dl related to an estimated decrease of 4.3 Full Scale IQ points; estimated decreases for Verbal and Performance IQ were 3.4 and 4.5 points, respectively. AUC7 was significantly and negatively related to three WISC-III factor scores: Freedom from Distractibility, Perceptual Organization, and Verbal Comprehension; the association with Perceptual Organization was the strongest. Consistent with previous studies, the IQ/lead association is small relative to more powerful social factors. Findings offer support for lead's behavioral signature; perceptual-motor skills are significantly more sensitive to lead exposure than are the language-related aspects of intelligence.

A prospective study of birthweight and length of gestation in a population surrounding a lead smelter in Kosovo, Yugoslavia.

This paper tests the hypothesis that exposure to lead during pregnancy is associated with reduced intrauterine growth and an increase in preterm delivery. The sample comprises women, recruited at mid-pregnancy, residing in Titova Mitrovica, a lead smelter town, or in Pristina, a non-exposed town 25 miles away. Both towns are in the province of Kosovo, Yugoslavia. Mean blood lead concentrations (BPb's) at mid-pregnancy were 0.92 mumol/L (+/- 0.38, N = 401) in the exposed town and 0.27 mumol/L (+/- 0.09, N = 506) in the comparison town. No differences were found between towns for either birthweight or length of gestation. Mean birthweight was 3308 (+/- 566) grams in Titova Mitrovica and 3361 (+/- 525) grams in Pristina. Mean length of gestation was 274 (+/- 18.8) days in Titova Mitrovica and 275 (+/- 15.6) days in Pristina. After adjustment for the effects of potential confounders, no significant relationships were found between maternal BPb measured at mid-pregnancy, at delivery or in the umbilical cord and either birthweight, length of gestation, or preterm delivery (less than 37 weeks). We conclude that exposure to environmental lead does not impair fetal growth or influence length of gestation.

The Yugoslavia Prospective Lead Study: contributions of prenatal and postnatal lead exposure to early intelligence.

To investigate associations between the timing of lead (Pb) exposure on early intelligence, we examined the results of psychometric evaluations at ages 3, 4, 5, and 7 years, from 442 children whose mothers were recruited during pregnancy from a smelter town and a non-lead-exposed town in Yugoslavia. We compared the relative contribution of prenatal blood lead (BPb) with that of relative increases in BPb in either the early (0-2 years) or the later (from 2 years on) postnatal period to child intelligence measured longitudinally at ages 3 and 4 (McCarthy GCI), 5 (Wechsler Preschool and Primary Scale of Intelligence-Revised, WPPSI-R IQ), and 7 (Wechsler Intelligence Scale for Children-version III, WISC-III IQ), controlling for: Home Observation for Measurement of the Environment (HOME) quality; maternal age, intelligence, education, and ethnicity; and birthweight and gender. Elevations in both prenatal and postnatal BPb were associated with small decrements in young children's intelligence.

Consequences of lead exposure and iron supplementation on childhood development at age 4 years.

For a prospective study of lead exposure and early development, we recruited pregnant women from a smelter town and a nonlead-exposed town in Yugoslavia and followed them and their children through age 4. For 332 children seen at age 4, mean scores on the McCarthy Scales General Cognitive Index (GCI) in the exposed and nonexposed towns were 81.3 and 86.6, respectively; geometric mean blood lead concentrations (BPb) were 39.9 and 9.6 micrograms/dl, respectively. Potential confounders included the quality of the HOME environment; maternal age, intelligence, education, and language; birthweight and gender. These showed predictable associations with 4-year intelligence, accounting for 42.7% of the variance in GCI. Following adjustment for these variables and for concurrent Hgb, we found significant independent adverse associations between GCI and BPb's, measured at 6-month intervals since birth. At age 4, BPb accounted for an incremental 3.5% of the variance in GCI, such that the estimated loss in GCI associated with an increase in BPb from 10-25 micrograms/dl was 3.8 points. The Perceptual-Performance subscale of the McCarthy was most sensitive to Pb exposure, a result consistent with findings from prospective studies in Boston and Port Pirie.

Depressed serum erythropoietin in pregnant women with elevated blood lead.

During the course of a prospective study of lead exposure and pregnancy outcome in 1,502 women, we tested the hypothesis that environmental lead exposure is associated with depressed serum erythropoietin concentration. At mid-pregnancy and at delivery, blood samples were stratified by hemoglobin concentration; within each hemoglobin stratum, sera of women with the lowest and highest whole blood lead concentrations were selected for serum erythropoietin analysis. Analysis of variance revealed that women with higher blood lead levels had inappropriately low serum erythropoietin at both mid-pregnancy and at delivery. Thus, depressed serum erythropoietin appears to indicate lead nephrotoxicity, and it may also be responsible for the anemia associated with lead poisoning.

Placental cadmium and birthweight in women living near a lead smelter.

It has been suggested that the accumulation of tobacco-derived cadmium (Cd) in the placenta is responsible for the adverse effect of cigarette smoking on infant birthweight. We chose to test this hypothesis; therefore, we studied a population of nonsmoking pregnant women who were exposed to low levels of smelter-derived Cd and a group of nonexposed women. A higher mean placental Cd concentration (p less than .0007) was found in the exposed women (n = 106), compared with those who were not exposed (n = 55); the observed Cd concentrations were comparable to concentrations reported previously for smoking and nonsmoking women, respectively. Least squares multiple regression (controlling for potentially confounding variables) revealed no association between placental Cd and birthweight. It was, therefore, concluded that the effect of smoking on birthweight was not mediated through Cd.

Elevated blood lead in a population near a lead smelter in Kosovo, Yugoslavia.

A survey of residents of a community surrounding a lead smelter has revealed an alarming incidence of elevated blood lead and erythrocyte protoporphyrin concentrations. In particular, children who were less than 3 yr of age were severely affected. Of those children tested in December, 1980, 35% had blood lead concentrations between 50-69 microgram/dl, while an additional 12% had concentrations greater than or equal to 70 microgram/dl, and are, therefore, at risk for severe neurological sequelae.

[Real effect of specific hyposensitisation in therapy of allergic respiratory diseases]. / Realni ucinak imunoterapije u respiracionoj alergiji.

There are different opinions on the positive effect of hyposensitisation in the treatment of allergic respiratory diseases. In this paper we wish to point out our experience, without intention to clear up these "contrary opinions". Sixty patients of both sexes, aged from 10-55 years, were on specific hyposensitisation over a period from three to five years. Two thirds (63%) were with bronchial asthma and 37% with allergic rhinitis. Most of them (80%) were on specific hyposensitisation to one allergen (Dermatophagoides pteronyssinus, grass or reguid polen), and to two allergens 20% patients. During this therapy 63% of patients had no additional medicamentae therapy. Most of them stopped additional medication during the first year of immunotherapy. Ten percent of patients took medicaments when they needed them, and 28% took them continually. Clinical symptoms characteristic of these diseases were also rare. The average value of IgE was 636 UI/ml before and 341 UI/ml after the immunotherapy. The efficacy of immunotherapy depended on the correct selection of patients, good standardisation of antigen extract, and a right dose of allergen in the prolonged immunotherapy.

[Results of Visiren administration in patients with respiratory infections]. / Rezultati primene Vizirena kod obolelih od respiracionih infekcija.

One of the most frequent causes of deterioration of chronic obstructive lung diseases is the infection. The existence of microorganisms resistant to antibiotics is becoming an increasingly serious therapeutical problem. Kinolones have a wider spectrum of action than the majority of other antibiotics, with strong effect on multiresistant gram-negative and gram-positive bacteria. Visirene (Ophloxacine) is a new antibiotic in this group. The efficiency of Visirene in the treatment of acute infections of the upper and lower respiratory organs, and acute deterioration or chronic obstructive lung diseases due infections, were investigated. The treatment was carried out on 30 patients in outpatient services. In all patients the appearance and duration of symptoms characteristic for the infection of the respiratory organs were examined (cough, coughing out, increase of body temperature, physical lung findings, dyspnea). The isolation of the causative agent was made from the sputum, throat and nose smears. Medical treatment began only if findings and antibiogram results were positive. The positive effect of Visirene was manifested in rapid withdrawal of symptoms and disappearance of bacteria in the sputum 7-10 day after the beginning of its administration. The administration of the drug provoked no side effects in these thirty patients. All findings suggested a very good effect of Visirene (Ophloxacine) in the treatment of infections of the respiratory system.

[Hyposensitization and antihistamines in the treatment of bronchial and allergic rhinitis]. / Hiposenzibilizacija i antihistaminici u lecenju bronhijalne astme i alergijskog rinitisa.

The control of symptoms in patients with allergic rhinitis and bronchial asthma can not be always attained with hyposensitization. This may be achieved with more success with additional treatment with H1 antagonists of histamine receptors. By hyposensitization statistically significant decrease of the total IgE was achieved. Contrary to this, in cases in which the symptoms could not be controlled with hyposensitization, only antihistamines were additionally administered, no significant decrease of IgE took place. These were, probably, more severe cases in which the symptoms could not be controlled with the hyposensitization only. No significant effect on the values of blood eosinophiles was registered with hyposensitization or additional administration of antihistamines.

[Use of Runac in patients with infections of the lower respiratory tract]. / Primena Runaca u obolelih od infekcija donjih disajnih puteva.

Thirty patients went through the outpatient treatment. Causative agent was established in sputum, throat and nose smears of 26 patients. Streptococcus pneumoniae (56%) and Haemophilus influenze (30%) are mostly isolated. Good effects of the medicine is characteristic by quick withdrawal of the symptoms characteristic for respiratory tract infections (cough and expectoration, febrility, physical finding) as well as by debacillosis after 10 days therapy. The effective result of medicine has been particularly noticed through quick reduction until complete disappearance of expectoration after three to four days since the onset of treatment. No side effects of the medicine have been found.

[The number of chronic patients contributing to total tuberculosis morbidity in the area of the city of Belgrade]. / Ucesce hronicnih bolesnika u ukupnom morbiditetu tuberkuloze sa podrucja grada Beograda.

During four years (from 1984-1987) a group of 94 patients with chronic pulmonary tuberculosis were investigated. Mean age of patients was 51 years-the youngest was 27 and the oldest 78. Mean time of disease was 5.4 years. They made 4.8% of all bacteriologically positive nonchronic patients. One third of them were resistant to one, 18% on two, 22% on three and 10% on all known antituberculosis drugs. It is very interesting that 19 patients or 20% were sensitive to all known antituberculosis drugs but tuberculosis still persisted.

Treatment of lead poisoning by 2,3-dimercaptosuccinic acid.

2,3-Dimercaptosuccinic acid (D.M.S.), a new orally effective agent for the treatment of heavy-metal intoxication, was administered to five lead-poisoned smelter workers for six days at dosages ranging from 8.4--12.7 mg/kg/day on the first day to 28.1--42.2 mg/kg/day on the last day. Mean blood-lead concentration decreased significantly from an initial value of 97 +/- 6 microgram/dl to 43 +/- 4 microgram/dl on the last day. Urinary lead excretion was significantly raised. D.M.S. was very well tolerated with no signs of toxicity and no effect on urinary zinc, calcium, magnesium, or iron excretion. Urinary copper excretion was significantly increased, but the magnitude of that effect was not clinically important. D.M.S. seems to be safe and effective for the treatment of lead poisoning.

Hypoxemia reflexly increases secretion from tracheal submucosal glands in dogs.

We anesthetized dogs, ventilated their lungs via the lower trachea, and exposed the epithelial surface of the upper trachea and coated it with powdered tantalum. Secretions from submucosal gland ducts formed elevations (hillocks) in the tantalum layer; we counted the number of hillocks that appeared in a 1.2-cm2 field. In 12 dogs, during normoxemia, 12 +/- 2 hillocks/cm2 formed in 90 s; during severe hypoxemia [fractional inspired O2 concentration (FIO2) = 0.05], 40 +/- 4 hillocks/cm2 formed in 90 s. Injections of sodium cyanide (25-75 micrograms) into the arterial supply to the carotid body also stimulated tracheal submucosal gland secretion. Secretory response to hypoxemia was suppressed by 1) section of both carotid sinus body nerves in six dogs and 2) section of both superior laryngeal nerves and vagus nerves in six other dogs. During mild hypoxemia (FIO2 = 0.10 or 0.15) tracheal submucosal gland secretion still increased. We conclude that hypoxemia increases secretion from submucosal glands in canine trachea by a carotid body chemoreflex.

The effect of lead exposure on behavior problems in preschool children.

OBJECTIVES: Interpreting associations between lead exposure and child behavior problems is difficult because studies have not controlled for sociodemographic confounders or have used shed teeth to mark exposure. This study explored associations between blood lead and preschool behavior. METHODS: Children from a smelter town and a non-lead-exposed town in Yugoslavia were followed up prospectively from pregnancy through age 3. The Child Behavior Checklist was used to assess behavior problems in 379 3-year-olds, controlling for sociodemographic factors and difficult infant temperament. RESULTS: Multiple regression revealed the expected significant associations between checklist subscales and sociodemographic factors, which explained 7% to 18% of the variance on the subscales. Concurrent blood lead explained a significant 1% to 4% of the variance on the Destructive and Withdrawn subscales. Earlier difficult temperament explained an additional 2% to 5% of the checklist variance. Scores on the Destructive subscale were consistently associated with blood lead. As blood lead increased from 10 to 20 micrograms/dL, subscale scores increased by approximately 0.5 points. CONCLUSIONS: Lead/behavior associations are significant but small compared with the effects of social factors.

Tibia lead levels and methodological uncertainty in 12-year-old children.

In vivo bone lead measurements with 109Cd-based K-shell X-ray fluorescence (XRF) have been used to assess long-term lead exposure in adults. Tibia lead levels were measured in 210 children (106 boys, 104 girls) of 11-12(1/2) years of age in a lead smelter town and in a control (nonexposed) town. Tibia lead levels, methodological uncertainties, and models of some of the factors influencing them are presented. 109Cd-based K-shell XRF tibia lead methodological uncertainty in children is comparable to that in adults.

Independent effects of lead exposure and iron deficiency anemia on developmental outcome at age 2 years.

For a prospective study of lead exposure, iron status, and infant development, we recruited infants living in a smelter town and a non-lead-exposed town in Kosovo, Yugoslavia. Among 392 infants assessed at age 2 years, the mean Mental Development Index (MDI), Bayley Scales of Infant Development, was 105.2. At age 2 years, geometric mean blood lead concentrations were 35.5 and 8.4 micrograms/dl, respectively, among infants from the exposed and nonexposed towns. After controlling for variables associated with MDI, we found significant independent associations for both blood lead and hemoglobin concentrations. For example, a rise in blood lead concentration at age 2 years from 10 to 30 micrograms/dl was associated with an estimated 2.5 point decrement in MDI (p = 0.03); statistically nonsignificant decrements were associated with blood lead levels measured at birth and at 6, 12, and 18 months of age. A decrease in hemoglobin concentration at 18 months of age from 12 to 10 gm/dl was associated with an estimated 3.4 point decrement in MDI (p = 0.02); the latter association was present in both towns, suggesting that it was due to iron deficiency anemia independent of lead exposure. The findings suggest that the brain is vulnerable to the effects of both lead exposure and anemia before 2 years of age. On a global basis, the developmental consequences of anemia may exceed those of lead exposure.

Past pregnancy outcomes among women living in the vicinity of a lead smelter in Kosovo, Yugoslavia.

This analysis compares the rates of spontaneous abortion among women living in the vicinity of a lead smelter with those of women living in a town where blood lead levels were low. Data derive from the obstetric histories of both groups of women obtained while seeking prenatal care for a later pregnancy. A total of 639 women (304 exposed, 335 unexposed) had at least one previous pregnancy and lived at the same address since their first pregnancy. The geometric mean blood lead concentrations in the sample at the time of the interviews were 0.77 mumol/L in the exposed town and 0.25 mumol/L in the unexposed town. The rates of spontaneous abortions in first pregnancies were similar, with 16.4 percent of women in the exposed town and 14.0 percent in the unexposed town reporting loss. The adjusted odds ratio relating town of residence to spontaneous abortion was 1.1 (95% CI = 0.9, 1.4). This analysis represents the first systematic attempt to seek an association between environmental lead exposure and spontaneous abortion. As such, the failure to find a positive association strongly suggests that at the levels of exposure represented in our sample, such an association does not exist.