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Re: Dichlorodiphenyltrichloroethane. Implications of Eskenazi et al study to malaria control in Africa.

Eskenazi-B; Marks-AR; Bradman-A; Johnson-C; Jewell-NP
Pediatrics 2006 Aug; 118(1):P3R2243
We thank Dr. Kahiira for his commendations and comments. We try to address each of his concerns below: 1. Concern that we did not control for nutritional status of children, in particular hemoglobin status: Although a child's hemoglobin status may be related to neurodevelopment, there is no evidence in the literature that iron deficiency is related to DDT exposure, and therefore it is not likely to be a true confounder. Nevertheless, we re-ran our models controlling for iron deficiency based on hematocrit values recorded in the medical record near the time of the assessments. We found that iron deficiency was not associated directly with DDT or Bayley scores and did not change the observed associations with DDT/E. 2. Concern that we did not control for maternal depression in some models: Based on the literature, we considered maternal depressive symptoms as a possible confounder in all analyses. As described in the paper, a variable was included in the multivariate models if it was related to the outcome at p<0.10 or changed the coefficient for DDT or DDE by at least 10%.[1] The only Bayley model in which there was even a weak association with maternal depression was with psychomotor development index (PDI) at 24 months. Thus, the variable for maternal depressive symptoms was not included in the mental developmental index (MDI) models because it did not fulfill these criteria. 3. Concern that we did not adjust for multiple comparisons: We first note that Dr. Kahiira misread our findings in that we had 7 (not 2) negative associations at p<0.05: o,p'-DDT with MDI at 12 and 24 months (p<0.01); p,p'-DDT with MDI at 12 and 24 months (p<0.05); p,p'-DDT with PDI at 6 and 12 months (p<0.05); and p,p'-DDE with PDI at 6 months (p<0.05)(Table 3 of manuscript[1]). While Dr. Kahiira raises an important issue with regard to adjustment for multiple comparisons, this is not as serious a concern as it might appear at first glance. Because of the interrelationships amongst the exposures and amongst the outcomes, the 18 comparisons shown in Table 3[1] are not independent. The serum levels of the three analytes (p,p-DDT, o,p, -DDT, and p,p-DDE) were highly correlated (pairwise r=0.8 to 0.9; p<0.001 [1]); we reported their findings separately because their high degree of collinearity prevented us from modeling them simultaneously. In addition, MDI and PDI were moderately correlated at each of the three time points (r=0.3 to 0.6; p<0.001) and, although not as strong, across ages (r=0.1 to 0.3; p<0.04). Thus, a Bonferroni correction might be considered unduly conservative. [2] Nevertheless, even employing a Bonferroni adjustment for six independent comparisons (allowing for independence of outcomes but not of exposures), our findings for MDI and o,p,-DDT at 12 (p=0.004) and 24 months (p=0.007) would still be considered "statistically significant" at =0.05. Further, the evaluation of the relationship of DDT and neurodevelopment should not focus solely on the issue of statistical significance. While perhaps not clinically relevant on an individual level, a few points on the Bayley MDI scale may be relevant at a population level. That is, a downward shift in the distribution of a population's neurodevelopmental scores could result in a larger fraction of children falling in the tail of the distribution with clinically significant developmental problems. 4. Concern about the relevance of our findings to current use of DDT for malaria control: A recent study of DDT levels in breastmilk in South African women living in regions where DDT has been used for IRS[3] suggest that exposures are at least as high as those in our study (adjusting for the ratio of DDT in breastmilk and serum[4]), which were associated with decrements in child neurodevelopment. However, it is not possible to determine the specific sources and pathways of DDT exposure in these populations, which may be due to environmental contamination from agricultural use, residues in the food supply, broadcast applications for public health purposes, or indoor uses on nets or interior residual spraying (IRS) for malaria control. To date, surprisingly little quantitative data have been published about the specific contribution of IRS to human DDT exposure. Dr. Kahiira reports that DDT readily breaks down to DDE in the high temperatures of tropical countries, and therefore, he concludes, there is less concern about DDT use given that our findings with DDE were weaker. However, IRS is recommended every six to twelve months[5] and repeated DDT spraying may lead to continuous exposure. Given its long half-life in humans (~6 years[6]), DDT might accumulate in the human body with regular use even if it breaks down to a less biologically active product in the environment. Again, empirical data on the specific contribution of IRS to human DDT exposures is needed. The cost of malaria in terms of human suffering is undeniably high. We are not in a position to endorse a particular policy regarding the use of DDT as an efficacious method for controlling this horrific disease, but rather we offer our research to help inform those who are making such policy decisions. Clearly, our research, the first to study the association between neurodevelopment and DDT, needs to be confirmed in other populations, and the children in our study should be followed to determine if our findings persist as the children enter the school years. Exposure in human populations should be monitored and potential health consequences should be studied to inform policy.
In-utero-exposure; Children; Demographic-characteristics; Racial-factors; Prenatal-exposure; Agriculture; Agricultural-industry; Agricultural-workers; Farmers
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University of California, Berkeley