Evelyn F. Robertson

Port Pirie Cohort Study: Environmental Exposure to Lead and Children's Abilities at the Age of Four Years

We studied the effect of environmental exposure to lead on childrens abilities at the age of four years in a cohort of 537 children born during 1979 to 1982 to women living in a community situated near a lead smelter. Samples for measuring blood lead levels were obtained from the mothers antenatally, at delivery from the mothers and umbilical cords, and at the ages of 6, 15, and 24 months and then annually from the children. Concurrently, the mothers were interviewed about personal, family, medical, and environmental factors. Maternal intelligence, the home environment, and the childrens mental development (as evaluated with use of the McCarthy Scales of Childrens Abilities) were formally assessed. The mean blood lead concentration varied from 0.44 mumol per liter in midpregnancy to a peak of 1.03 mumol per liter at the age of two years. The blood lead concentration at each age, particularly at two and three years, and the integrated postnatal average concentration were inversely related to development at the age of four. Multivariate analysis incorporating many factors in the childrens lives indicated that the subjects with an average postnatal blood lead concentration of 1.50 mumol per liter had a general cognitive score 7.2 points lower (95 percent confidence interval, 0.3 to 13.2; mean score, 107.1) than those with an average concentration of 0.50 mumol per liter. Similar deficits occurred in the perceptual-performance and memory scores. Within the range of exposure studied, no threshold dose for an effect of lead was evident. We conclude that postnatal blood lead concentration is inversely related to cognitive development in children, although one must be circumspect in making causal inferences from studies of this relation, because of the difficulties in defining and controlling confounding effects.

Neonatal screening for cystic fibrosis using immunoreactive trypsinogen and direct gene analysis: four years' experience.

Abstract Objective : To assess the performance and impact of a two tier neonatal screening programme for cystic fibrosis based on an initial estimation of immunoreactive trypsinogen followed by direct gene analysis. >Design : Four year prospective study of two tier screening strategy. First tier: immunoreactive trypsinogen measured in dried blood spot samples from neonates aged 3-5 days. Second tier: direct gene analysis of cystic fibrosis mutations (δF508, δI506, G551D, G542X, and R553X) in samples with immunoreactive trypsinogen concentrations in highest 1% and in all neonates with meconium ileus20or family history of cystic fibrosis. Setting : South Australian Neonatal Screening Programme, Adelaide. Subjects : All 88 752 neonates born in South Australia between December 1989 and December 1993. Interventions : Neonates with two identifiable mutations were referred directly for clinical assessment and confirmatory sweat test; infants with only one identifiable mutation were recalled for sweat test at age 3-4 weeks. Parents of neonates identified as carriers of cystic fibrosis mutation were counselled and offered genetic testing. Main outcome measures - Identification of20all children with cystic fibrosis in the screened population. Results : Of 1004 (1.13%) neonates with immunoreactive trypsinogen >=99th centile, 912 (90.8%) had no identifiable mutation. 23 neonates were homozygotes or compound heterozygotes; 69 carried one identifiable mutation, of whom six had positive sweat tests. Median age at clinical assessment for the 29 neonates with cystic fibrosis was 3 weeks; six had meconium ileus and two had affected siblings. 63 neonates were identified as carriers of a cystic fibrosis mutation. Extra laboratory costs for measuring immunoreactive trypsinogen and direct gene analysis were

Port Pirie Cohort study: childhood blood lead and neuropsychological development at age two years.

A1.50 per neonate screened. Conclusion : This strategy results in early and accurate diagnosis of cystic fibrosis and performs better than screening strategies based on immunoreactive trypsinogen measurement alone.

Sociodemographic factors modifying the effect of environmental lead on neuropsychological development in early childhood

The Port Pirie Cohort Study is an ongoing prospective study of the relationship between exposure to environmental lead within a lead smelter community, and neuropsychological development in early childhood. Over 600 children, originally recruited during antenatal life, underwent serial blood lead estimations up to two years of age. Systematic interview information was collected on a range of variables, and formal developmental assessment (Bayley Scales of Infant Development) was carried out at 24 months of age. Blood lead concentrations measured antenatally (maternal), at delivery (maternal and umbilical cord) and postnatally at 6, 15 and 24 months were negatively correlated (p less than 0.05) with mental development at 24 months of age. Geometric mean blood lead concentrations (microgram/dl) were 14.3, 20.8 and 21.2 at 6, 15 and 24 months of age respectively. When multiple covariates, including maternal IQ, were controlled for in multiple regression analysis, a statistically significant (p less than 0.01) inverse association was observed between blood lead concentration (PbB) measured at 6 months of age and mental development at 2 years of age. No such association was evident for psychomotor development. When the quality of the home environment (HOME Score) was added to the multiple regression model, the inverse association between blood lead concentration at 6 months of age and mental development at 2 years persisted, albeit less strongly (p = 0.07). From this analysis, it is estimated that a child with with PbB of 30 micrograms/dl at age 6 months will have a deficit of 3.3 points (approximately 3%) on the Bayley Mental Development Scale relative to a child with PbB of 10 micrograms/dl.

Lead in the placenta, membranes, and umbilical cord in relation to pregnancy outcome in a lead-smelter community

A long-term prospective cohort study was conducted to examine the association between prenatal and postnatal exposure to environmental lead and childhood neuropsychological development. The possible interactive effects of blood lead and some covariates on early development were explored in this study. Our data suggest that gender of the child modifies the effect of lead on the neuropsychological development during early childhood. At the ages of 2 and 4 years, girls appear to be more sensitive than boys to the neuropsychological effects of lead. However, there is no significant modification of the effect of lead by some other covariates, such as parental smoking, socioeconomic status, home environment, birth weight, and the kind of infant feeding. Evidence of interactions between environmental lead exposure and other covariates in the causation of neuropsychological deficits in childhood underscores the desirability of considering both main effects and interactions in this area of research. Such effects, if confirmed, may have implications for public health intervention strategies.

Pathology of hepatic peroxisomes and mitochondria in patients with peroxisomal disorders

As part of a cohort study of the effects of chronic exposure to lead on pregnancy outcome and child development, lead concentrations in the umbilical cord and placental tissues (body and membranes) from 9 late fetal deaths, 23 preterm births, and 18 births associated with premature rupture of the amniotic membranes were compared with the lead concentrations in the tissues obtained at 22 normal births. Modest elevations in lead concentration were found in the placental body of late fetal deaths (stillbirths) and preterm births as well as in the cord tissue associated with preterm births and premature rupture of membranes. The geometric mean lead concentration in the membranes from late fetal deaths was 2.73 micrograms/g of dry tissue (95% confidence limits 0.69-10.8), which was 3.5 times higher than the mean found in normal births (0.78 micrograms/g, 95% confidence limits 0.61-1.00). The concentration in the membranes of preterm births was also significantly high, being 1.24 micrograms/G (0.91-1.67). Low correlations of membrane and antenatal blood lead concentrations suggest that other factors in addition to exposure to environmental lead may influence the amount of lead accumulated in the placental membranes.

Exposure to environmental lead and visual-motor integration at age 7 years: the Port Pirie Cohort Study.

The morphology of hepatic peroxisomes in five patients with metabolic disorders believed to be due to inherited defects of peroxisomal function or biogenesis is described. Electron microscopy and cytochemical staining for catalase were used to identify peroxisomes in two boys with infantile Refsums disease (IRD), a girl with autopsy confirmed neonatal adrenoleukodystrophy (NALD), and two boys with pseudo-Zellweger syndrome (PZS). In the patients with IRD and NALD hepatic peroxisomes were significantly reduced in size and number and contained electron dense centres. In the liver of the patients with PZS the peroxisomes were enlarged. Morphologically abnormal peroxisomes were also detected in autopsy tissue from one boy with PZS using electron microscopy. Lamellar-lipid inclusions and mitochondria with crystalline inclusions and/or abnormal cristae are also described in two patients, one with IRD, the other with NALD.

The sensitivity of ultrasound and serum alpha-fetoprotein in population-based antenatal screening for neural tube defects, South Australia 1986–1991

Early childhood exposure to environmental lead may result in subtle deficits in neuropsychological development. Most studies, however, have reported global measures of development, and the findings have not been consistent. In this report, we examine the association between blood lead concentration and a specific aspect of neuropsychological development, visual-motor integration. Each child in a cohort of 494 children living in and around the lead smelting town of Port Pirie, South Australia, was followed for its first 7 years of life. Serial blood samples were collected at various ages to estimate the lifetime burden of each individual. At the time of each blood sampling, systematic information was obtained on a wide range of other variables relevant to child development. We evaluated visual-motor integration at age 7 with the Beery Developmental Test of Visual-Motor Integration (mean score: 13.4). There was an inverse relation between blood lead concentration and visual-motor performance. After adjustment for potential confounding factors, both prenatal and postnatal blood lead concentrations exhibited a dose-related inverse association with childrens visual-motor performance. For an increase in lifetime average blood lead concentration from 10 μag per dl (0.48 μmol per liter) to 30 μg per dl (1.45 μmol per liter), the estimated deficit in childrens visual-motor performance was 1.6 points (95% confidence interval = 0.3–2.9). The results indicate that visual-motor integration may be a more sensitive index than global measures of development, such as intelligence quotient, for the assessment of lead effects on child development.

Treatment of infantile phytanic acid storage disease: clinical, biochemical and ultrastructural findings in two children treated for 2 years

Objective To determine the sensitivity of antenatal screening methods for neural tube defects in population‐based screening in South Australia in 1986–1991, and whether ultrasound can replace serum alpha‐fetoprotein screening in terms of achieving an equivalent level of sensitivity.

Variable distributions of serum creatine kinase reference values

Two patients with infantile phytanic acid storage disease (infantile Refsum disease), one of whom showed the presence of morphologically normal peroxisomes in a liver biopsy, were treated with a low phytanic acid diet for more than 2 years and the effects of treatment on certain clinical, biochemical and ultrastructural parameters were examined. Both patients showed evidence of either an improvement or stabilisation in their clinical condition. Plasma phytanic acid levels decreased to near normal values in approximately 6 weeks after the introduction of the diet; plasma pipecolic acid also declined markedly but the decrease was not so rapid and its level remained abnormal. C26∶C22 fatty acid ratios decreased very slowly and even after 2 years the values remained grossly abnormal. Despite the marked reduction of phytanic acid in the liver, there was an increase in the C26∶C22 fatty acid ratios and this appeared to be paralleled by an increase in inclusion bodies. Our data suggest that some patients with the infantile form of Refsum disease may show some clinical benefit from dietary management and this is reflected biochemically by decreases in the plasma levels of phytanic acid and pipecolic acid.