Spatial distribution of EEG theta activity as a function of lifetime lead exposure in 9-year-old children.

The relationship between low-level childhood lead exposure and developmental retardation has been proposed but the existing evidence is weak. We examined the EEG of 42 children participating in the Mexico City Prospective Lead Study to determine if relative theta power and distribution across the scalp was related to history of lifetime lead exposure as measured by sequential blood lead concentration of the mother during pregnancy and the child after delivery. EEG was recorded from scalp electrodes placed according to the 10-20 system during eyes-closed. Theta activity (4-7 Hz) was filtered with a fast Fourier transform (FFT) and relative power calculated. The expected distribution of theta was found, with the greatest relative power centrally located and lesser amounts at frontal, occipital, and lateral derivations. Multiple regression models of theta at each electrode showed that increasing postnatal blood lead from 6 to 96 months was related to increasing relative theta power adjusted for age, sex and fetal suffering at delivery, in occipital derivations. The most significant increases in theta power were associated with blood lead levels (geometric mean = 10.3 microg/dl) measured between 54 and 72 months. Spatially weighted regression demonstrated that there was a significant antero-posterior gradient in lead-induced increase in relative theta power associated with postnatal blood lead levels at 54-72 months and 78-96 months. The greatest lead effect on both occipital relative theta power and the antero-posterior gradient of theta power was found with lead at an age during which relative theta power reaches its developmental maximum and starts to decrease. Results suggest that 54-72 months represent a critical period during which lead can exert lasting effects on the developmental pattern of theta activity. Occipital derivation of the largest effects of lead on theta activity may also be related to other lead-related developmental deficits.

Temporal pattern in the effect of postnatal blood lead level on intellectual development of young children.

To determine the temporal pattern of the effect of postnatal blood lead level on the General Cognitive Index (GCI) of the McCarthy Scales of Children's Abilities, we used data from 112 children of the Mexico City Prospective Lead Study with complete evaluations from 36 to 60 months of age at 6-month intervals. We measured blood lead level every 6 months from 6 to 54 months. We controlled for 5-min Apgar, birth weight, birth order, sex, socioeconomic level, maternal IQ, and maximum maternal educational level in a repeated measures ANCOVA using child blood lead level grouped by 6-18 month (geometric mean 10.1 microg/dl, range 3.5-37.0 microg/dl), 24-36 month (geometric mean 9.7 microg/dl, range 3.0-42.7 microg/dl), and 42-54 month (geometric mean 8.4 microg/dl, range 2.5-44.8 microg/dl) averages. There were significant interactions between the 6-18 month blood lead level and age with GCI as the endpoint and between 24-36 month blood lead level and age. The regression coefficient of blood lead at 6-18 months became more negative with age until 48 months, when the rate of decline moderated (linear polynomial contrast p=0. 047). The regression coefficient of blood lead at 24-36 months with CGI became more negative as well from 36 to 48 months but then started decreasing toward zero from 48 to 60 months (quadratic polynomial contrast p=0.019). Significant between-subjects lead effects on GCI were found for 24-36 month blood lead level at 48 months (p=0.021) and at 54 months (p=0.073). The greatest effect (at 48 months) was a 5.8-point GCI decrease with each natural log unit increase in blood lead. Significant between-subjects lead effects on GCI were found for 42-54 month blood lead level at 54 months (p=0. 040) and at 60 months (p=0.060). The effect of postnatal blood lead level on GCI reaches its maximum approximately 1-3 years later, and then becomes less evident. Four to five years of age appears to be a critical period for the manifestation of the earlier postnatal blood lead level effects.

Blood lead secular trend in a cohort of children in Mexico City. II. 1990-1995.

The authors determined the secular trend in blood lead levels in a cohort of 91 children born in Mexico City between 1987 and the beginning of 1993. The authors grouped children by calendar year in which they reached 36 mo of age (i.e., 1990-1995), and their blood lead levels were measured every 6 mo during a 66-mo period. The overall geometric mean blood lead level was 8.6 microg/dl (range = 1.0-61.0 microg/dl). A repeated measures analysis of variance revealed a significant downward linear trend in blood lead levels by year (p < .001)--from an estimated marginal geometric mean of 14.2 microg/dl in 1990 to 6.3 microg/dl in 1995. There was also a significant linear age effect (p < .001); blood lead levels generally fell during the 36th-66th mo. Family use of lead-glazed pottery significantly elevated blood lead levels (p = .006), and the effect magnified as age increased (Age x Pottery Interaction [p = .014]). Although the overall downward trend in blood lead levels during the time period described corresponded to a reduction in various sources of lead exposure, there was no alteration in production, distribution, or use of leaded pottery. Currently, use of lead-glazed ceramic pottery is one of the most profound sources of lead exposure in the Mexican population.

Brainstem auditory evoked response at five years and prenatal and postnatal blood lead.

Previous work from this laboratory demonstrated an association between higher maternal blood lead level at 20 weeks of pregnancy and increased I-V and III-V interpeak intervals in the brainstem auditory evoked response (BAER) recorded in 1-month-old infants. We repeated the BAER measurements with a larger group of children (n = 100-113) from the same study at 5-7 years. Maternal blood lead level at 20 weeks of pregnancy (geometric mean = 7.7 microg/dl; range 1-30. 5 microg/dl) was the only prenatal blood lead level significantly associated with I-V and III-V interpeak interval in a multiple regression model controlling for head circumference and age at time of testing and sex. In contrast to the findings at 1 month of age, interpeak intervals decreased as a linear function of increasing 20-week maternal blood lead. A nonlinear, orthogonal, second-order polynomial model was a significantly better fit to the data than the linear model. The nonlinear model showed I-V and III-V interpeak intervals decreased as blood lead rose from 1 to 8 microg/dl, and then increased as blood lead rose from 8 to 30.5 microg/dl. We hypothesized that the negative linear term was related to lead effect on brainstem auditory pathway length, and that the positive quadratic term was related to neurotoxic lead effect on synaptic transmission or conduction velocity. We found support for the brainstem length interpretation in the data, showing that 6-year-old head circumference in these children significantly decreased with increased maternal 20-week blood lead level. Increasing postnatal blood lead at 12 and 48 months was related only to decreased BAER conduction intervals across the entire blood lead range, suggesting only pathway length effects. Alterations in BAER at this age may indicate that the effect of prenatal lead exposure on the auditory brainstem is permanent, as response latencies reach essentially adult values by 4 years of age.

Lead-glazed ceramic ware and blood lead levels of children in the city of Oaxaca, Mexico.

Although Mexico substantially reduced use of leaded gasoline during the 1990s, lead-glazed pottery remains a significant source of population exposure. Most previous studies of lead in nonoccupationally exposed groups in Mexico have been conducted in the Mexico City metropolitan area. Oaxaca, a poor southern state of Mexico, has a centuries-old tradition of use of low temperature lead-glazed ceramic ware manufactured mainly by small family businesses. We measured blood lead levels in 220 8-10-y-old children (i.e., not from pottery-making families) who were students in the innercity of Oaxaca and in the mothers of all children. The geometric mean blood lead level of the children was 10.5 microg/dl (+7.0/-4.3 microg/dl standard deviation; range = 1.3-35.5 microg/dl). The corresponding mean value for the mothers was 13.4 (+9.0/-5.4 microg/dl standard deviation; range = 2.8-45.3 microg/dl). We used cutoffs that were greater than or equal to 10 microg/dl, 20 microg/dl, and 30 microg/dl, and we determined that 54.9%, 10.3%, and 3.0% of the children were at or above the respective criteria. We accounted for 25.2% of the variance in blood lead levels of the children, using maternal responses to a questionnaire that assessed possible lead sources in a linear multiple-regression model. The most important factors related to lead levels were family use of lead-glazed pottery, use of animal fat in cooking, and family income. The addition of maternal blood lead level to the model increased accounted variance in blood lead to 48.0%. In logistic-regression modeling of children's blood lead levels, we used a cutoff of greater than or equal to 10 microg/dl, and we found that use of lead-glazed pottery was the most important of all questionnaire items that were predictive of blood lead levels (odds ratio = 2.98). In Oaxaca, as is the case elsewhere in Mexico, lead-glazed ceramic ware remains a significant risk factor for elevated blood lead levels in children.

Determinants of bone and blood lead concentrations in the early postpartum period.

OBJECTIVE: This study investigated determinants of bone and blood lead concentrations in 430 lactating Mexican women during the early postpartum period and the contribution of bone lead to blood lead. METHODS: Maternal venous lead was measured at delivery and postpartum, and bone lead concentrations, measured with in vivo K-x ray fluorescence, were measured post partum. Data on environmental exposure, demographic characteristics, and maternal factors related to exposure to lead were collected by questionnaire. Linear regression was used to examine the relations between bone and blood lead, demographics, and environmental exposure variables. RESULTS: Mean (SD) blood, tibial, and patellar lead concentrations were 9.5 (4.5) microg/dl, 10.2 (10.1) microg Pb/g bone mineral, and 15.2 (15.1) microg Pb/g bone mineral respectively. These values are considerably higher than values for women in the United States. Older age, the cumulative use of lead glazed pottery, and higher proportion of life spent in Mexico City were powerful predictors of higher bone lead concentrations. Use of lead glazed ceramics to cook food in the past week and increased patellar lead concentrations were significant predictors of increased blood lead. Patellar lead concentrations explained one third of the variance accounted for by the final blood lead model. Women in the 90th percentile for patella lead had an untransformed predicted mean blood lead concentration 3.6 microg/dl higher than those in the 10th percentile. CONCLUSIONS: This study identified the use of lead glazed ceramics as a major source of cumulative exposure to lead, as reflected by bone lead concentrations, as well as current exposure, reflected by blood lead, in Mexico. A higher proportion of life spent in Mexico City, a proxy for exposure to leaded gasoline emissions, was identified as the other major source of cumulative lead exposure. The influence of bone lead on blood lead coupled with the long half life of lead in bone has implications for other populations and suggests that bone stores may pose a threat to women of reproductive age long after exposure has declined.

Pre- and postnatal lead effect on head circumference: a case for critical periods.

We examined the association of maternal prenatal [range of median blood lead level 7.5-9.0 microg/dl (0.36-0.43 micromol/l) during pregnancy] and child postnatal blood lead level [range of median blood lead level from birth to 48 months 7.0-10.0 microg/dl (0.34-0.48 micromol/l)] with head circumference in from 119 to 199 children from the Mexico City Prospective Lead Study. We used repeated multiple regression modeling with a standard set of control variables, entering blood lead level last. Using Bonferroni-corrected probability values to control for inflation of Type I error due to multiple testing at each age, we found significant negative associations (p<0.05, two-tailed) between 6-month head circumference and 36-week maternal blood lead level, and 36-month head circumference and 12-month blood lead level. Over the 25-75% interquartile range of measured blood lead, head circumference decreased around 0.4 cm. Over the 1-35 microg/dl (0.05-1.68 micromol/l) range of maternal blood lead at 36 weeks, the estimated reduction in 6-month head circumference was 1.9 cm (95% CI = 0.9-3.0 cm). These results suggest that children are more vulnerable to certain effects of lead exposure at specific age ranges, and that the effect of lead on head circumference only becomes evident for brief periods in the first 4 years of life. We discuss various artifacts as well as possible mechanisms by which lead might have produced the observed pattern of results. We suggest that higher lead exposure prevalent several decades ago might have subtly influenced published normative human growth data.

Secular trend in blood lead levels in a cohort of Mexico City children.

We determined the secular trend in blood lead levels in a cohort of 104 children born in Mexico City between 1987 and 1993. We grouped children by the calendar year in which they reached 6 mo of age and measured blood lead levels every 6 mo until they attained 36 mo of age. The overall geometric mean blood lead level was 9.6 microg/dl (range = 1.5-59.5 microg/dl). A repeated measures analysis of variance revealed a highly significant linear trend in blood lead level with year (p < .001); there was a maximum decrease of 7.6 microg/dl between 1989 and 1993. There was a highly significant quadratic age effect (p < .001); blood lead levels rose between 6 and 18 mo of age and decreased thereafter. There was a marginally significant interaction between age of the child and year. Family use of lead-glazed pottery significantly elevated blood lead levels (p = .028). The downward trend in blood lead levels during the time period of study corresponded to the reduction in various sources of lead exposure.

Umbilical cord beta-endorphin and early childhood motor development.

Stress during delivery has been associated with elevated umbilical cord plasma beta-endorphin levels. Published research suggests that much cord beta-endorphin originates from fetal pituitary. Intact pituitary function is required for normal growth and development. Relationships between cord beta-endorphin and child development have not been previously reported. We measured paired maternal and cord plasma beta-endorphin concentration in a set of 106 low risk deliveries by solid phase two-site immunoradiometric assay. Geometric mean maternal and cord beta-endorphin concentrations were 128 pg/ml and 196 pg/ml, respectively, with corresponding ranges of 33-533 pg/ml and 70-579 pg/ml. Cord beta-endorphin concentration was significantly higher than maternal, regardless of delivery mode, and the two were significantly correlated (r = 0.231; P = 0.017). Multiple regression modeling showed that forceps delivery, maternal beta-endorphin concentration, bradycardia, vaginal delivery, and birth weight each made independent contributions to elevated cord beta-endorphin. Depressed cord beta-endorphin predicted more day 2 neurological soft signs, lower 6-month mental development, and lower 36-month motor score on psychometric tests of the children. Poorer fine motor control and coordination were predominantly associated with lower beta-endorphin. Level of cord beta-endorphin independent of delivery stress exerted the primary influence upon child motor development. Higher levels of stress-independent beta-endorphin may play a direct role in motor development.

Maternal influences on cord blood lead levels.

We constructed models of umbilical cord blood lead (PbB), with and without the addition of maternal PbB at delivery and earlier in pregnancy, to determine which factors explaining cord PbB depended upon maternal PbB and which did not. We prospectively studied women of low-to-middle socioeconomic status who lived in the Valley of Mexico from 12 weeks of pregnancy to delivery. We measured maternal venous PbB during pregnancy and at delivery, and umbilical cord PbB (1-38 micrograms/dl, 0.05-1.83 mumol/l). We used multiple regression analyses to model cord PbB and a logit analysis to model the maternal-cord PbB relationship. Older mothers using lead-glazed pottery and canned foods delivered babies with increased cord PbB, while those with occasional alcohol use during pregnancy, high milk intake, and more spontaneous abortions delivered babies with lower cord PbB. Maternal PbB at 36 weeks of pregnancy and at delivery independently explained additional variance in cord PbB, but maternal PbB earlier in pregnancy did not. Some of the effects of lead-glazed pottery, maternal abortions, alcohol use, and canned food use on cord PbB were mediated through maternal PbB. The effects of maternal age and milk intake on cord PbB were independent of their influence on maternal PbB near delivery. Cord PbBs were higher than maternal PbBs at delivery in 33% of the cases, and were predominant in mothers over 30 and those drinking milk less than once per day. Measurable influence of maternal PbB on delivery cord PbB is limited to the four to eight weeks prior to delivery. Many factors suspected of influencing bone lead also control cord PbB, some of them independently of their effect on maternal delivery PbB. Minimizing fetal exposure near the end of pregnancy may require long-term control of maternal lead exposure and good management of pregnancy and diet.

Prenatal and perinatal lead exposures alter acoustic cry parameters of neonate.

We performed acoustic analyses on cries elicited from a subset of healthy babies born to the Mexico City Prospective Lead Study at 2 days (n = 75), 15 days (n = 176), and 30 days (n = 166). Lead was measured in maternal blood every 8 weeks during pregnancy from week 12 to delivery and in umbilical cord (1-38 micrograms/dL, 0.05-1.84 mumol/L). Percent nasalization and number of cries decreased in babies born to mothers with higher lead levels in the last two trimesters while median fundamental frequency increased in babies born to mothers with higher lead at 12 weeks of pregnancy, and with higher cord lead in multiple regression analysis. Decreased percent nasalization was related to increased brainstem auditory evoked response latencies and interpeak intervals in a subset of the sample. The results suggest an effect of gestational exposure to lead on apparatus innervated by cranial nerves and/or lead effect on cry mediated by lead-altered auditory function. Altered baby cry and auditory function associated with lead might contribute to developmental delays by affecting early communication between caretaker and baby.

Changes in serial blood lead levels during pregnancy.

The first step in modeling lead kinetics during pregnancy includes a description of sequential maternal blood lead (PbB) during pregnancy and the factors controlling it. We analyzed PbB of 105 women living in the Valley of Mexico from week 12 to week 36 of pregnancy and again at parturition. We also used data from all women contributing blood at any stage of pregnancy to determine antecedents of PbB. Pregnancies were uneventful, and offspring were normal. Although geometric mean PbB level averaged around 7.0 micrograms/dl (0.34 mumol/l), with a range of 1.0-35.5 micrograms/dl throughout pregnancy, analysis of variance revealed a significant decrease in mean PbB from week 12 to week 20 (1.1 micrograms/dl) and various significant increases in mean PbB from week 20 to parturition (1.6 micrograms/dl). Regression analyses confirmed the positive linear PbB trend from 20 weeks to parturition and additional contributions of dietary calcium, reproductive history, lifetime residence of Mexico City, coffee drinking, and use of indigenous lead-glazed pottery. Although decreasing hematocrit has been suggested to explain first-half pregnancy PbB decrease, the time course of hematocrit decrease in the present study did not match the sequential changes in PbB. While hemodilution and organ growth in the first half of pregnancy may account for much of the PbB decrease seen between 12 and 20 weeks, the remaining hemodilution and accelerated organ growth of the last half of pregnancy do not predict the trend toward increasing maternal PbB concentration from 20 weeks to delivery. Mobilization of bone lead, increased gut absorption, and increased retention of lead may explain part of the upward PbB trend in the second half of pregnancy. Reduction of lifetime lead exposure may be required to decrease risk of fetal exposure.

Neurobehavioral deficits after low level lead exposure in neonates: the Mexico City pilot study.

Gestation age and ability of the baby to self-quiet and to be consoled during the first 30 days of life decrease when mother's blood lead levels rise from 36 weeks of pregnancy to birth of child. These effects appear to be independent of the absolute lead levels of mother and child (N = 42). Since pre- and perinatal stress predicts higher maternal birth lead, further work could determine the relative contributions of undetected stress during pregnancy and elevated lead levels upon subsequent development. Several cases, not included in the statistical analyses, showed associations between cord leads greatly elevated over maternal leads and poor outcome.