Comments on "Recent Developments in Low-Level Lead Exposure and Intellectual Impairment in Children"
[citation in pubmed]
We commend Koller et al. (2004) for their thoughtful and detailed review of recent research on childhood lead exposure and intellectual development, and we take this opportunity to clarify and respond to several of their questions regarding our study of children with blood lead concentrations < 10 µg/dL) (Canfield et al. 2003).
The children in our cohort were recruited between 24 and 30 months of age, and all had participated in a prior randomized dust control trial (Lanphear et al. 1999). In that trial, dust and blood lead concentrations were assessed at 6, 12, 18, and 24 months of age as part of an evaluation of whether dust control measures reduced children's blood lead concentrations. Koller et al. (2004) raised several questions related to whether children's participation in the prior study affected the results we reported (Canfield et al. 2003). Specifically, their concerns related to confounding, where an imbalance in the distribution of intervention/control participants across levels of blood lead and IQ could bias the association between blood lead concentrations and IQ.
Our statistical model was developed a priori and included covariates that were established predictors of children's intelligence (Canfield et al. 2003). Because home visitation by a dust control team (intervention) seemed unlikely to increase children's IQ and because children who participated in the intervention actually had slightly lower IQ scores at 3 and 5 years of age compared with controls, intervention status was not considered a plausible confounder. To demonstrate that participation in the dust control trial did not introduce any bias of consequence and to illustrate our basis for excluding intervention status from our published models, in this letter we summarize results for a semiparametric spline model, which is identical to the one we reported previously (Canfield et al. 2003) except for the inclusion of intervention status as a potential confounding factor. The estimated decline in IQ as blood lead concentration increases from 1 to 10 µg/dL is 6.8 points when controlling for intervention status. This estimate is not meaningfully different from the 7.4-point decline we reported previously (Canfield et al. 2003). Furthermore, the shape of the dose-response function is preserved, with a steeper slope at lower blood lead concentrations. Estimates of the predicted decline in IQ from parametric models with linear and quadratic terms for blood lead also differ by < 10% from the reported results (Canfield et al. 2003) when intervention status is included in the model.
Additionally, Koller et al. (2004) suggested that the Stanford-Binet IV Test of Intelligence (SBIV) may not have provided the most accurate estimate of IQ for our cohort because of the relative weighting of verbal and nonverbal skills that are assessed and because of problems with the standard method of dealing with zero-scored subtests. Koller et al. (2004) suggested that the Wechsler Primary and Preschool Scales of Intelligence (WPPSI) would have yielded a more reliable and valid measure of intelligence. We first note that despite many attractive features of the WPPSI (and especially of the WPPSI-Revised, which we considered using), the SBIV has features that we believe made it a superior test for our particular cohort. Most importantly, the SBIV can be administered to 2-year-olds, whereas the youngest age for the WPPSI-R is 3 years. Because our sample was predominantly composed of families with lower parental education and income, we preferred the test with the lower floor.
With respect to how zero-scored subtests are handled, we indeed followed the standard scoring procedure for the SBIV, which states that a zero score "should not be included in the determination of the related Area Score or of the Composite Score" (Delaney and Hopkins 1987). Because this scoring method was used in the standardization of the instrument, a different approach would yield scores with unknown psychometric properties and thereby compromise interpretation of the results.
Nevertheless, any particular scoring method has its weaknesses, and we agree that it would be useful to know whether our results change markedly by incorporating information about zero scores. We therefore added as a time-varying covariate in our mixed models the number of subtests on which each child scored zero. In the semiparametric spline model, the estimated decline in IQ as blood lead concentration increased from 1 to 10 µg/dL was 6.3 points. Estimates from parametric models with linear and quadratic terms for blood lead differed by < 5% from the results we reported previously (Canfield et al. 2003). Thus, the incorporation of information about zero-scored subtests did not change our results markedly.
Potential sources of confounding and misclassification need to be carefully considered in the design and analysis phase of any study, observational or otherwise, and in the interpretation of results. The detailed attention given to these issues by Koller et al. (2004) has allowed us the opportunity to provide additional information about our methods and results and thereby address these methodologic issues.
Bruce P. Lanphear has acted as an expert witness for several plaintiffs in lead cases, but he has not received financial remuneration; instead, any payment has been donated directly to the Cincinnati Children's Hospital Medical Center. The other authors declare they have no competing financial interests.
Todd A. Jusko
Department of Epidemiology
University of Washington
Seattle, Washington
E-mail: jusko@u.washington.edu
Richard L. Canfield
Division of Nutritional Sciences
Cornell University
Ithaca, New York
Charles R. Henderson, Jr.
Department of Human Development
Cornell University
Ithaca, New York
Bruce P. Lanphear
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio
References
Canfield RL, Henderson CR Jr, Cory-Slechta DA, Cox C, Jusko TA, Lanphear BP. 2003. Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter. N Engl J Med 348:1517-1526.
Delaney DA, Hopkins TF. 1987. The Stanford-Binet Intelligence Scale: Fourth Edition Examiner's Handbook. Chicago:The Riverside Publishing Company.
Koller K, Brown T, Spurgeon A, Levy L. 2004. Recent developments in low-level lead exposure and intellectual impairment in children. Environ Health Perspect 112:987-994.
Lanphear BP, Howard C, Eberly S, Auinger P, Kolassa J, Weitzman M, et al. 1999. Primary prevention of childhood lead exposure: a randomized trial of dust control. Pediatrics 103:772-777.
Low-Level Lead Exposure and Intellectual Impairment in Children: Koller et al. Respond
[citation in pubmed]
We are grateful to Jusko et al. for addressing two concerns raised in our review (Koller et al. 2004) relating to confounding and their use of the Stanford-Binet test in their original report (Canfield et al. 2003). They provide valuable additional analysis of their data, which further support their original findings.
Of relevance to the area of confounding is a recent publication by Mink et al. (2004) in which the effects of different combinations of confounders on multivariate analyses of neurobehavior and neurotoxic exposure were studied. Taking maternal intelligence, home environment, and socioeconomic status as the three most important confounders in this field, Mink et al. urged caution in associating small differences in IQ score in the range of 3-10 points with the effects of environmental exposure; they also made a strong case for a priori consideration and planning for all potential confounders in epidemiological studies. As Jusko et al. explain, this is indeed the method they used in their original analyses (Canfield et al. 2003).
We feel that the weight of evidence across a number of studies has come down in support of an effect of low-level lead exposure on children's intellectual and neurobehavioral function; as stressed by Bellinger (2004), this evidence is supported by studies on experimental animals in which confounding is largely irrelevant.
The authors declare they have no competing financial interests.
Karin Koller
Len Levy
Terry Brown
MRC Institute for Environment & Health
University of Leicester
Leicester, United Kingdom
E-mail: kew13@le.ac.uk
Anne Spurgeon
Institute of Occupational Health
University of Birmingham,
Birmingham, United Kingdom
References
Bellinger DC. 2004. Assessing environmental neurotoxicant exposures and child neurobehavior: confounded by confounding? Epidemiology 15:383-384.
Canfield RL, Henderson CR Jr, Cory-Slechta DA, Cox C, Jusko TA, Lanphear BP. 2003. Intellectual impairment in children with blood lead concentrations below 10 microg per deciliter. N Engl J Med 248:1517-1526.
Koller K, Brown T, Spurgeon A, Levy L. 2004. Recent developments in low-level lead exposure and intellectual impairment in children. Environ Health Perspect 112:987-994.
Mink PJ, Goodman M, Barraj LM, Imrey H, Kelsh MA, Yager J. 2004. Evaluation of uncontrolled confounding in studies of environmental exposures and neurobehavioral testing in children. Epidemiology 15:385-393.
TCDD and Puberty in Girls
[citation in pubmed]
We would like to comment on the article by Warner et al. (2004), in which the authors reported no significant associations between age at menarche and exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an extremely potent antiestrogenic xenobiotic. The exposure of girls to TCDD at Seveso, Italy, resulted in very high serum TCDD levels (> 100 pg/g lipid), 10-100 times levels usually seen today. Warner et al. noted that the literature is mixed regarding the agonist/antagonist effects in humans of persistent exposures of this type. First, polybrominated biphenyl exposures have been associated with earlier menarche in girls, whereas experimental models show delayed puberty, a discordance that may be due to timing of exposure (Blanck et al. 2000). Second, as Warner et al. (2004) noted, the experimental data show that TCDD and other estrogen antagonists delay vaginal opening (VO) and disrupt cyclicity in rodents treated prenatally (Gray et al. 1997; Levy et al. 1995). However, hormonal activity depends on both timing and level of dose, such that phytoestrogens, for example, may be estrogenic--hastening VO--at high doses given after birth (Lamartiniere et al. 1995; Whitten et al. 1995).
Epidemiologic data regarding hormonally dependent female cancer are equivocal, such that there have been suggestions of a protective (i.e., antiestrogenic) effect of TCDD for breast and uterine cancer in TCDD-exposed women from Seveso (Bertazzi et al. 2001), whereas a carcinogenic effect has been observed in cohorts exposed for longer times (Manz et al. 1991; Warner et al. 2002). The findings of Warner et al. (2004), albeit not statistically significant, suggest earlier menarche with higher TCDD level among women who were younger than 8 years of age at the time of exposure [hazard ratio, 1.08 for 10-fold increase in TCDD levels; 95% confidence interval (CI), 0.89-1.30) but not among all women regardless of age. The study population appears to have the usual patterns of risk for menarche as indicated by associations that occur in the expected directions [e.g., for Seveso zone, body mass index (BMI), physical activity, alcohol intake]. Also, TCDD levels were higher among younger girls (median, 205 ppt) than in all girls (median, 140 ppt), an effect that may reflect lower BMI among younger girls and dilution of body burden by greater body size in older girls, but also a significantly higher target-organ dose.
Warner et al. (2004) examined associations in premenarcheal girls who were a younger subset (0-8 years of age) during the exposure window in 1976. This age stratum should capture any strong underlying associations among girls exposed early in life. However, it is known that pubertal transition occurs around 5-7 years of age and that age at menarche is strongly correlated with age at first signs of development (de Ridder et al. 1992; Nicolson and Hanley 1953). Therefore, hormonal exposures before 5 years of age might alter the milestones of female development, including menarche, either more potently or in a different direction than peripubertal exposures. Therefore, the youngest girls in this population (Warner et al. 2004) may have been more susceptible to hormonal effects of environmental toxicants. Recognizing the limitation of small numbers available for further age stratification, it would be interesting to know whether risk of earlier (or later) puberty was raised among girls exposed at earlier ages, such as 0-4 years.
The authors declare they have no competing financial interests.
Mary S. Wolff
Julie A. Britton
Mount Sinai School of Medicine
New York, New York
E-mail: mary.wolff@mssm.edu
Jose Russo
Fox Chase Cancer Center
Philadelphia, Pennsylvania
References
Bertazzi PA, Consonni D, Bachetti S, Rubagotti M, Baccarelli A, Zocchetti C, et al. 2001. Health effects of dioxin exposure: a 20-year mortality study. Am J Epidemiol 153:1031-1044.
Blanck HM, Marcus M, Tolbert PE, Rubin C, Henderson AK, Hertzberg VS, et al. 2000. Age at menarche and tanner stage in girls exposed in utero and postnatally to polybrominated biphenyl. Epidemiology 11:641-647.
de Ridder CM, Thijssen JH, Bruning PF, Van den Brande JL, Zonderland ML, Erich WB. 1992. Body fat mass, body fat distribution, and pubertal development: a longitudinal study of physical and hormonal sexual maturation of girls. J Clin Endocrinol Metab 75:442-446.
Gray LE, Wolf C, Mann P, Ostby JS. 1997. In utero exposure to low doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin alters reproductive development of female Long Evans hooded rat offspring. Toxicol Appl Pharmacol 146:237-244.
Lamartiniere CA, Moore JB, Brown NM, Thompson R, Hardin MJ, Barnes S. 1995. Genistein suppresses mammary cancer in rats. Carcinogenesis 16:2833-2840.
Levy JR, Faber KA, Ayyash L, Hughes CL Jr. 1995. The effect of prenatal exposure to the phytoestrogen genistein on sexual differentiation in rats. Proc Soc Exp Biol Med 208:60-66.
Manz A, Berger J, Dwyer JH, Flesch-Janys D, Nagel S, Waltsgott H. 1991. Cancer mortality among workers in chemical plant contaminated with dioxin. Lancet 338: 959-964.
Nicolson AB, Hanley C. 1953. Indices of physiological maturity: derivation and interrelationships. Child Dev 24:3-38.
Warner M, Eskenazi B, Mocarelli P, Gerthoux PM, Samuels S, Needham L, et al. 2002. Serum dioxin concentrations and breast cancer risk in the Seveso Women's Health Study. Environ Health Perspect 110: 625-628.
Warner M, Samuels S, Mocarelli P, Gerthoux PM, Needham L, Patterson DG Jr, et al. 2004. Serum dioxin concentrations and age at menarche. Environ Health Perspect 112: 1289-1292.
Whitten PL, Lewis C, Russell E, Naftolin F. 1995. Phytoestrogen influences on the development of behavior and gonadotropin function. Proc Soc Exp Biol Med 208: 82-86.
TCDD and Puberty: Warner and Eskenazi Respond
[citation in pubmed]
As Wolff et al. note, in data from the Seveso Women's Health Study (SWHS) we found no change in age of onset of menarche associated with TCDD exposure in all women in the cohort or in women exposed before 8 years of age (Warner et al. 2004). However, Wolff et al. comment that hormonal exposures before 5 years of age might be the more relevant time period, given that the pubertal transition occurs around 5-7 years of age. Recognizing that our data may be limited by small numbers, Wolff et al. are interested in knowing whether risk of earlier (or later) puberty was seen among girls who were exposed before 5 years of age.
Of the 282 women in the SWHS cohort who were premenarcheal at the time of the explosion on 10 July 1976, 84 women were < 5 years of age. The mean age of menarche reported for the 84 women was 12.6 ± 1.5 years, and the median lipid-adjusted serum TCDD level was 233 ppt (range, 3.6-56,000 ppt). In Cox proportional hazards models, when log10TCDD was entered as the exposure variable, the hazard ratio associated with a 10-fold increase in TCDD was 1.2 [95% confidence interval, 0.98-1.6; p for trend = 0.07]. That is, the risk of early menarche was increased with the presence of a 10-fold increase in serum TCDD level (e.g., from 10 to 100 ppt), but not significantly. The data were too sparse in the lower exposure groups to perform categorical analyses. The observed increase was limited to the subset of women who were < 5 years of age at exposure, as the effect was diminished when we considered including older ages (< 6 years, < 7 years).
In summary, the sample size is too small to state with certainty, but it seems that the women who received higher exposure and were < 5 years of age at the time of the explosion may have been at somewhat increased risk for earlier menarche. As we stated in our article (Warner et al. 2004), the women in this study experienced significant TCDD exposure during the postnatal but prepubertal developmental period. Given that animal evidence suggests in utero exposure can affect onset of puberty, continued follow-up of the offspring of the SWHS cohort is important.
The authors declare they have no competing financial interests.
Marcella Warner
Brenda Eskenazi
School of Public Health
University of California-Berkeley
Berkeley, California
E-mail: mwarner@calmail.berkeley.edu
Reference
Warner M, Samuels S, Mocarelli P, Gerthou PM, Needham L, Patterson DG Jr, et al. 2004. Serum dioxin concentrations and age at menarche. Environ Health Perspect 112: 1289-1292.
Comment on "Breast Milk: An Optimal Food"
[citation in pubmed]
In their editorial "Breast Milk: An Optimal Food," Pronczuk et al. (2004) stated that "in most cases, mothers can and should be reassured that breast milk is by far the best food to give to their babies," despite the evidence that "a myriad of potential chemical contaminants . . . can be detected in breast milk," mainly because a) levels of environmental contaminants, as determined by subsequent surveys, continue to decrease; b) exposure through breast milk may be less important than exposure in utero; and c) there is little evidence that exposure through breast milk is associated with damage.
We believe that there is probably a fourth good reason in support of their recommendation. There is in fact some evidence that breast-feeding may counteract some of the negative effects of exposure to environmental contaminants in utero.
For example, Boersma and Lanting (2000) showed that at 6 years of age cognitive development is affected by prenatal exposure to polychlorinated biphenyls (PCBs) and dioxins. Breast-fed children, however, when compared to formula-fed children, had an advantage in terms of quality of movements, fluency, and cognitive development tests at 18 and 42 months of age and at 6 years of age, despite a higher PCB exposure from breast milk.
Ribas-Fito et al. (2003), studying a birth cohort of 92 mother-infant pairs highly exposed to organochlorine compounds, found that prenatal exposure was associated with a delay in mental and psychomotor development at 13 months of age and that long-term breast-feeding counterbalanced this damage because it was associated with better performance on both the mental and motor scales compared to short-term or no breast-feeding.
Vreugdenhil et al. (2004) found that children who were breast-fed for at least 16 weeks did not show the delays in development of the central nervous system that are present in children breast-fed for 6-16 weeks or formula-fed, despite a similar prenatal exposure to PCBs.
This evidence is not conclusive (scientific evidence rarely is), but we believe that it should not be omitted in an article on environmental contaminants and breast-feeding.
The authors declare they have no competing financial interests.
Adriano Cattaneo
Unit for Health Services Research and International Health
Child Health Institute
Trieste, Italy
E-mail: cattaneo@burlo.trieste.it
Maryse Lehners
Initiativ Liewensufank
Itzig, Luxemburg
E-mail: maryse.lehners@education.lu
References
Boersma ER, Lanting CI. 2000. Environmental exposure to polychlorinated biphenyls (PCBs) and dioxins. Consequences for longterm neurological and cognitive development of the child lactation. Adv Exp Med Biol 478: 271-287.
Pronczuk J, Moy G, Vallenas C. 2004. Breast milk: an optimal food [Editorial]. Environ Health Perspect 112:A722-A723.
Ribas-Fito N, Cardo E, Sala M, Eulalia dM, Mazon C, Verdu A, et al. 2003. Breastfeeding, exposure to organochlorine compounds, and neurodevelopment in infants. Pediatrics 111:e580-e585.
Vreugdenhil HJ, Van Zanten GA, Brocaar MP, Mulder PG, Weisglas-Kuperus N. 2004. Prenatal exposure to polychlorinated biphenyls and breastfeeding: opposing effects on auditory P300 latencies in 9-year-old Dutch children. Dev Med Child Neurol 46:398-405.
Editor's note: In accordance with journal policy, Pronczuk et al. were asked whether they wanted to respond to this letter, but they chose not to do so.
Errata
Because the study "Threshold of Trichloroethylene Contamination in Maternal Drinking Waters Affecting Fetal Heart Development in the Rat" (Johnson et al. 2003) was a long-term and continuous study, the authors compiled the data from controls of several treatment groups. The control "sets" were statistically analyzed comparing the data to each other before being combined. The authors opine that the control values were statistically consistent across and throughout all the treatment groups. Using the control data in a cumulative manner increased the generalizability of the data, which purports to demonstrate the background rate and variability around rate estimates. The larger sample size somewhat increased statistical power without the inappropriate use of further valuable animal resources.
Table 1.
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Table 1 presents the date ranges of experimental treatment and the coinciding control treatments. Each treatment exposure had a corresponding control group. Also, because of the more detailed information on competing financial interests now included in EHP's Instructions to Authors, the authors now report that S.J. Goldberg served as an expert witness for a plaintiff in a judicial hearing in 1997. As previously stated in a prior letter to the editor (Johnson et al. 2004), at all times throughout this research, the authors were free to design, conduct, interpret, and publish the research without compromise by any controlling sponsor as a condition of review or publication.
References
Johnson PD, Dawson BV, Goldberg SJ. 1998a. Cardiac teratogenicity of trichloroethylene metabolites. J Am Coll Cardiol 32(2):540-545.
Johnson PD, Dawson BV, Goldberg SJ. 1998b. A review: trichloroethylene metabolites: potential cardiac teratogens. Environ Health Perspect 106(suppl 4):995-999.
Johnson PD, Dawson BV, Goldberg SJ, Mays MZ. 2004. Trichloroethylene: Johnson et al.'s Response [Letter]. Environ Health Perspect 112:A608-A609.
Johnson PD, Goldberg SJ, Mays MZ, Dawson BV. 2003. Threshold of trichloroethylene contamination in maternal drinking waters affecting fetal heart development in the rat. Environ Health Perspect 111:289-292.
In "Environmental Health Disparities: A Framework Integrating Psychosocial and Environmental Concepts" by Gee et al. [Environ Health Perspect 112:1645-1653 (2004)], the title of Figure 1 should be "Stress-exposure disease framework for environmental health disparities."
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Last Updated: December 15, 2004