- Email: [email protected]
Effect of polychlorinated biphenyls on psychodevelopment
CORRESPONDENCE
5
Lackmann GM, Angerer J, Töllner U. Parental smoking and neonatal serum levels of polychlorinated biphenyls and hexachlorobenzene. Pediatr Res 2000; 47: 598–601.
Sir—Jens Walkowiak and colleagues1 have tested two general hypotheses: do environmental levels of exposure to PCBs adversely affect psychomotor and mental development during early childhood; and, if such effects are found, can they be counteracted by a favourable home environment? These hypotheses are indisputably non-directional, since both allow for results to occur in either direction. Consequently, the statistical tests must be interpreted as two-tailed probabilities. After several data analyses, Walkowiak and colleagues conclude that PCBs have a significantly negative impact on children’s psychomotor and mental development from age 30 months onward, and the quality of the home environment has a significant positive effect on psychomotor and mental development, also from age 30 months onwards. Unfortunately, these results cannot be ascribed scientific validity because of some serious design flaws. First, the researchers state that they used one-tailed probabilities throughout, because the hypotheses were directional, and effects at p<0·05 were significant. Adjusting for this flaw means doubling each of the reported probability levels. This required adjustment2 changes the results strikingly. Of nine comparisons involving PCBs, six were significant with one-tailed tests, but only two remained significant with the two-tailed tests. Furthermore, the research scientist must then adjust for the nine post-hoc PCB comparisons that were done to eliminate the mistake of misinterpreting chance for significant probability. After this adjustment, no PCB comparison comes close to significance. By contrast, Walkowiak and colleagues also made nine comparisons involving home environment; again, six were significant before but only five remained significant after two-tailed tests were done; three were still significant after adjustment for the nine multiple comparisons. But even if most PCB results, like the home results, had remained significant, that still would not be sufficient. The major difficulty is that the home environment needs to be treated as a confounding variable, as it has been in other PCB3 and lead-level4 investigations, rather than as a separate independent variable. Joseph and Sandra Jacobson5 point to the importance of
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adjusting for potential confounders, especially the home environment, parental education, and maternal intelligence quotient. Furthermore, Walkowiak and colleagues note that the home environment is an influential confounder in neurotoxicity studies, which contradicts their curious decision to omit this factor as a confounder in their study. The essential scientific question must be, what is the effect, if any, of PCB concentrations on psychomotor and mental development, after the effects of home environment have been eliminated? I predict that even the unadjusted one-tailed significant PCB effects would become invalid, because, as the researchers correctly conclude, the overall positive impact of the home environment is stronger than the negative effect of neonatal PCB exposure. *Domenic V Cicchetti, Alan S Kaufman Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA (e-mail: [email protected]) 1
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3
4
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Walkowiak J, Wiener J-A, Fastabend A, et al. Environmental exposure to polychlorinated biphenyls and quality of the home environment: effects on psychodevelopment in early childhood. Lancet 2001; 358: 1602–07. Toothaker LE. Multiple comparisons for researchers. Newbury Park: Sage Publications, 1991. Pantandin S, Lanting CI, Mulder PGH, Boersma ER, Sauer PJJ, Weisglas-Kuperus N. Effects of environmental exposure to polychlorinated biphenyls and dioxins on cognitive abilities in Dutch children at 42 months of age. J Pediatr 1999; 134: 33–41. Kaufman AS. Do low levels of lead produce IQ loss in children? A careful examination of the literature. Arch Clin Neuropsychol 2001; 16: 303–41. Jacobson JL, Jacobson SW. Postnatal exposure to PCBs and childhood development. Lancet 2001; 358: 1568–69.
Authors’ reply Sir—Gerd-Michael Lackmann summarises our main findings incorrectly. We found negative associations between PCBs in milk taken at age 2 weeks, and Bayley or Kaufman test scores taken at ages 7, 18, 30, and 42 months. These early PCB values in milk reflect maternal body burden during pregnancy and, thus, prenatal exposure. We report also a pure postnatal impact of PCB for the Kaufman test at 42 months after adjustment for prenatal PCB exposure. The doubts about the validity of this pure postnatal association are understandable, because most studies stress the importance of prenatal exposure.
Thus, our observations require corroboration. However, Joseph and Sandra Jacobson do state that our observations are consistent with experimental data, which is one of the requirements for inferring causality from correlations.1 Lackmann believes that the small amounts of PCBs transmitted to fetuses or to infants produce no neurotoxic effects by themselves. However, he contradicts this by admitting that neurotoxic effects of PCBs were previously shown in relation to the small quantities transmitted across the placenta to the vulnerable developing brain. He suggests that smoking mothers or environmental tobacco smoke increase the prenatal uptake of PCBs and may have long-lasting effects. We included maternal smoking during pregnancy in our regression model. Lackmann is surprised that the serum PCB concentrations at age 42 months in bottle-fed infants were slighly lower than those in cord-blood values. In the group as a whole, the expected postnatal increase of PCB body burden does occur. The slight decrease in the small group of bottle-fed children is probably because of dilution related to rapid early growth, and the associated increase of fat compartments.2,3 Domenic Cicchetti and Alan Kaufman suggest inappropriate testing of nondirectional hypotheses, with no adjustment for multiple testing or quality of the home environment. Our hypotheses were directional. We tested for adversity of prenatal and neonatal PCB exposure, because the assumption of a beneficial impact of PCBs on motor and mental development is not biologically plausible. We also tested for a beneficial effect of the home environment because, for psychological reasons, good parental caretaking supports rather than impairs psychodevelopment. Thus, one-tailed testing is mandatory. Six of the nine comparisons made were significant. This is very unlikely to have occurred by chance alone (p<0·0001). Division of p values by nine would be necessary to correctly interpret only one of nine comparisons. In contrast to Cicchetti and Kaufman’s reasoning, we do not simply rely on p values and formal hypothesis testing to show negative developmental PCB effects; these criteria are judged least important in epidemiological reasoning.4,5 We, therefore, presented doseresponse information and effect sizes additionally and took into account possible sources of bias. Cicchetti and Kaufman may have misunderstood our statistical methods.
THE LANCET • Vol 359 • April 20, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.
5
Lackmann GM, Angerer J, Töllner U. Parental smoking and neonatal serum levels of polychlorinated biphenyls and hexachlorobenzene. Pediatr Res 2000; 47: 598–601.
Sir—Jens Walkowiak and colleagues1 have tested two general hypotheses: do environmental levels of exposure to PCBs adversely affect psychomotor and mental development during early childhood; and, if such effects are found, can they be counteracted by a favourable home environment? These hypotheses are indisputably non-directional, since both allow for results to occur in either direction. Consequently, the statistical tests must be interpreted as two-tailed probabilities. After several data analyses, Walkowiak and colleagues conclude that PCBs have a significantly negative impact on children’s psychomotor and mental development from age 30 months onward, and the quality of the home environment has a significant positive effect on psychomotor and mental development, also from age 30 months onwards. Unfortunately, these results cannot be ascribed scientific validity because of some serious design flaws. First, the researchers state that they used one-tailed probabilities throughout, because the hypotheses were directional, and effects at p<0·05 were significant. Adjusting for this flaw means doubling each of the reported probability levels. This required adjustment2 changes the results strikingly. Of nine comparisons involving PCBs, six were significant with one-tailed tests, but only two remained significant with the two-tailed tests. Furthermore, the research scientist must then adjust for the nine post-hoc PCB comparisons that were done to eliminate the mistake of misinterpreting chance for significant probability. After this adjustment, no PCB comparison comes close to significance. By contrast, Walkowiak and colleagues also made nine comparisons involving home environment; again, six were significant before but only five remained significant after two-tailed tests were done; three were still significant after adjustment for the nine multiple comparisons. But even if most PCB results, like the home results, had remained significant, that still would not be sufficient. The major difficulty is that the home environment needs to be treated as a confounding variable, as it has been in other PCB3 and lead-level4 investigations, rather than as a separate independent variable. Joseph and Sandra Jacobson5 point to the importance of
1438
adjusting for potential confounders, especially the home environment, parental education, and maternal intelligence quotient. Furthermore, Walkowiak and colleagues note that the home environment is an influential confounder in neurotoxicity studies, which contradicts their curious decision to omit this factor as a confounder in their study. The essential scientific question must be, what is the effect, if any, of PCB concentrations on psychomotor and mental development, after the effects of home environment have been eliminated? I predict that even the unadjusted one-tailed significant PCB effects would become invalid, because, as the researchers correctly conclude, the overall positive impact of the home environment is stronger than the negative effect of neonatal PCB exposure. *Domenic V Cicchetti, Alan S Kaufman Child Study Center, Yale University School of Medicine, 230 South Frontage Road, New Haven, CT 06520, USA (e-mail: [email protected]) 1
2
3
4
5
Walkowiak J, Wiener J-A, Fastabend A, et al. Environmental exposure to polychlorinated biphenyls and quality of the home environment: effects on psychodevelopment in early childhood. Lancet 2001; 358: 1602–07. Toothaker LE. Multiple comparisons for researchers. Newbury Park: Sage Publications, 1991. Pantandin S, Lanting CI, Mulder PGH, Boersma ER, Sauer PJJ, Weisglas-Kuperus N. Effects of environmental exposure to polychlorinated biphenyls and dioxins on cognitive abilities in Dutch children at 42 months of age. J Pediatr 1999; 134: 33–41. Kaufman AS. Do low levels of lead produce IQ loss in children? A careful examination of the literature. Arch Clin Neuropsychol 2001; 16: 303–41. Jacobson JL, Jacobson SW. Postnatal exposure to PCBs and childhood development. Lancet 2001; 358: 1568–69.
Authors’ reply Sir—Gerd-Michael Lackmann summarises our main findings incorrectly. We found negative associations between PCBs in milk taken at age 2 weeks, and Bayley or Kaufman test scores taken at ages 7, 18, 30, and 42 months. These early PCB values in milk reflect maternal body burden during pregnancy and, thus, prenatal exposure. We report also a pure postnatal impact of PCB for the Kaufman test at 42 months after adjustment for prenatal PCB exposure. The doubts about the validity of this pure postnatal association are understandable, because most studies stress the importance of prenatal exposure.
Thus, our observations require corroboration. However, Joseph and Sandra Jacobson do state that our observations are consistent with experimental data, which is one of the requirements for inferring causality from correlations.1 Lackmann believes that the small amounts of PCBs transmitted to fetuses or to infants produce no neurotoxic effects by themselves. However, he contradicts this by admitting that neurotoxic effects of PCBs were previously shown in relation to the small quantities transmitted across the placenta to the vulnerable developing brain. He suggests that smoking mothers or environmental tobacco smoke increase the prenatal uptake of PCBs and may have long-lasting effects. We included maternal smoking during pregnancy in our regression model. Lackmann is surprised that the serum PCB concentrations at age 42 months in bottle-fed infants were slighly lower than those in cord-blood values. In the group as a whole, the expected postnatal increase of PCB body burden does occur. The slight decrease in the small group of bottle-fed children is probably because of dilution related to rapid early growth, and the associated increase of fat compartments.2,3 Domenic Cicchetti and Alan Kaufman suggest inappropriate testing of nondirectional hypotheses, with no adjustment for multiple testing or quality of the home environment. Our hypotheses were directional. We tested for adversity of prenatal and neonatal PCB exposure, because the assumption of a beneficial impact of PCBs on motor and mental development is not biologically plausible. We also tested for a beneficial effect of the home environment because, for psychological reasons, good parental caretaking supports rather than impairs psychodevelopment. Thus, one-tailed testing is mandatory. Six of the nine comparisons made were significant. This is very unlikely to have occurred by chance alone (p<0·0001). Division of p values by nine would be necessary to correctly interpret only one of nine comparisons. In contrast to Cicchetti and Kaufman’s reasoning, we do not simply rely on p values and formal hypothesis testing to show negative developmental PCB effects; these criteria are judged least important in epidemiological reasoning.4,5 We, therefore, presented doseresponse information and effect sizes additionally and took into account possible sources of bias. Cicchetti and Kaufman may have misunderstood our statistical methods.
THE LANCET • Vol 359 • April 20, 2002 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet Publishing Group.