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Response to letter by Karmaus and Zhu
LETTER Response to Letter by Karmaus and Zhu In our paper, we examined 18 chemicals, specifically, 7 organochlorine pesticides and 11 polychlorinated biphenyls (PCBs), for possible relationships to birthweight, comparing mean birthweights among tertiles of each chemical (1). After adjustment for potential confounders, statistically significant differences among tertiles were seen only for β-hexachlorocyclohexane, and it had a non-monotonic pattern. We concluded that there was no convincing evidence in this population for an effect of these chemicals on birthweight. Karmaus and Zhu note that raw means for the tertiles of some chemicals displayed monotonic patterns; this should occur by chance one-third of the time, as there are six possible orderings, two of which are monotonic. They point out the cases of p,p’-DDE, which increased (with central and upper tertiles nearly identical), and PCB #187, which decreased (with lower and central tertiles nearly identical). Monotonic patterns also occurred for trans-nonachlor, heptachlor epoxide, and PCB #105. Patterns in the adjusted means were not necessarily the same. The greatest difference between lower and upper tertiles, whether adjusted or not, was seen for β-hexachlorocyclohexane. Karmaus and Zhu also note that exposures to the chemicals studied are typically correlated; they cite data from other populations but not from ours. We observed rank correlations above 0.6 between the pair p,p’-DDE and p,p’DDT, among the trio heptachlor epoxide, trans-nonachlor, and oxychlordane, and among six of the PCBs (2). All other correlations were lower. In particular, correlations between p,p’-DDE and the 11 PCBs ranged from ⫺0.03 to 0.51. Karmaus and Zhu suggest that there may be counterbalancing true effects, with one chemical increasing birthweight, another decreasing it, and observed effects attenuated by correlations. This is certainly theoretically possible; almost any pattern, including reversal of direction, can occur. Indeed, multiple chemicals, including some not measured, could be involved in complex ways. However, entertaining a hypothesis with effects in both directions based on post-hoc examination of results seems fraught with difficulties. In the absence of prior evidence, the potential for being led astray by chance patterns seems high. The available human literature, reviewed in our paper (1) or appearing more recently (3–7), suggests that the chemicals studied either have no effect on birthweight or are associated with decreases. Karmaus and Zhu propose an alternate analysis with a single model simultaneously including p,p’-DDE and the PCBs; it is not clear why they do not propose to include 쑕 2004 Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010
the remaining six chemicals. In the analysis they propose, the presence of very high correlations (some above 0.9) will make the results for the individual chemicals unreliable. Note also that this model would entail an assumption that effects are additive; while this may well be a reasonable approximation for effects in the same direction, it is perhaps less suitable for effects in different directions. Whether increases and decreases would cancel in a simple fashion would depend on the underlying biology. Disregarding any reservations and doing the proposed analysis does not produce the result that Karmaus and Zhu expect. Repeating the analysis of birth weight shown in Table 4, except for simultaneous inclusion of all 18 chemicals in a single model, yields no significant effects of any chemicals. Standard errors are all increased. The greatest changes in adjusted means are seen for some of the highly intercorrelated PCBs. Other changes are generally minor; for example, the adjusted means for the three tertiles of p,p’-DDE change from those in Table 4 by at most 1.1%. Including only the chemicals of interest to Karmaus and Zhu yields similar results, as does analysis of relative weight rather than birth weight. Thoughtful consideration of potential confounding is always important in observational studies. Under the hypothesis that the chemicals, if anything, decrease birthweight, the likely error from examination of single chemicals is misattribution of effects of one chemical to another correlated chemical or overestimation of effects by attributing the effects of both to one. Lacking evidence of any effects, it is unlikely that our analysis led us astray under this scenario. Beth Gladen Biostatistics Branch, NIEHS, NIH, DHHS, Research Triangle Park, NC, USA
REFERENCES 1. Gladen BC, Shkiryak-Nyzhnyk ZA, Chyslovska N, Zadorozhnaja TD, Little RE. Persistent organochlorine compounds and birth weight. Ann Epidemiol. 2003;13:151–157. 2. Gladen BC, Monaghan SC, Lukyanova EM, Hulchiy OP, Shkyryak-Nyzhnyk ZA, Sericano JL, et al. Organochlorines in breast milk from two cities in Ukraine. Environ Health Perspect. 1999;107:459–462. 3. Grandjean P, Bjerve KS, Weihe P, Steuerwald U. Birthweight in a fishing community: Significance of essential fatty acids and marine food contaminants. Int J Epidemiol. 2001;30:1272–1278.
1047-2797/04/$–see front matter doi:10.1016/j.annepidem.2003.09.007
AEP Vol. 14, No. 2 February 2004: 152–153
Beth Gladen LETTER
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4. Polder A, Odland JO, Tkachev A, Foreid S, Savinova TN, Skaare JU. Geographic variation of chlorinated pesticides, toxaphenes, and PCBs in human milk from sub-arctic and arctic locations in Russia. Sci Total Environ. 2003;306:179–195.
6. Siddiqui MKJ, Srivastava S, Srivastava SP, Mehrotra PK, Mathur N, Tandon I. Persistent chlorinated pesticides and intra-uterine foetal growth retardation: A possible association. Int Arch Occup Environ Health. 2003;76:75–80.
5. Ribas-Fito´ N, Sala M, Cardo E, Mazo¯n C, DeMuga ME, Verdu´ A, et al. Association of hexachlorobenzene and other organochlorine compounds with anthropometric measures at birth. Pediatr Res. 2002;52:163–167.
7. Torres-Arreola L, Berkowitz G, Torres-Sa´nchez L, Lo´pez-Cervantes M, Cebria´n ME, Uribe M, et al. Preterm birth in relation to maternal organochlorine serum levels. Ann Epidemiol. 2003;13:158–162.
the remaining six chemicals. In the analysis they propose, the presence of very high correlations (some above 0.9) will make the results for the individual chemicals unreliable. Note also that this model would entail an assumption that effects are additive; while this may well be a reasonable approximation for effects in the same direction, it is perhaps less suitable for effects in different directions. Whether increases and decreases would cancel in a simple fashion would depend on the underlying biology. Disregarding any reservations and doing the proposed analysis does not produce the result that Karmaus and Zhu expect. Repeating the analysis of birth weight shown in Table 4, except for simultaneous inclusion of all 18 chemicals in a single model, yields no significant effects of any chemicals. Standard errors are all increased. The greatest changes in adjusted means are seen for some of the highly intercorrelated PCBs. Other changes are generally minor; for example, the adjusted means for the three tertiles of p,p’-DDE change from those in Table 4 by at most 1.1%. Including only the chemicals of interest to Karmaus and Zhu yields similar results, as does analysis of relative weight rather than birth weight. Thoughtful consideration of potential confounding is always important in observational studies. Under the hypothesis that the chemicals, if anything, decrease birthweight, the likely error from examination of single chemicals is misattribution of effects of one chemical to another correlated chemical or overestimation of effects by attributing the effects of both to one. Lacking evidence of any effects, it is unlikely that our analysis led us astray under this scenario. Beth Gladen Biostatistics Branch, NIEHS, NIH, DHHS, Research Triangle Park, NC, USA
REFERENCES 1. Gladen BC, Shkiryak-Nyzhnyk ZA, Chyslovska N, Zadorozhnaja TD, Little RE. Persistent organochlorine compounds and birth weight. Ann Epidemiol. 2003;13:151–157. 2. Gladen BC, Monaghan SC, Lukyanova EM, Hulchiy OP, Shkyryak-Nyzhnyk ZA, Sericano JL, et al. Organochlorines in breast milk from two cities in Ukraine. Environ Health Perspect. 1999;107:459–462. 3. Grandjean P, Bjerve KS, Weihe P, Steuerwald U. Birthweight in a fishing community: Significance of essential fatty acids and marine food contaminants. Int J Epidemiol. 2001;30:1272–1278.
1047-2797/04/$–see front matter doi:10.1016/j.annepidem.2003.09.007
AEP Vol. 14, No. 2 February 2004: 152–153
Beth Gladen LETTER
153
4. Polder A, Odland JO, Tkachev A, Foreid S, Savinova TN, Skaare JU. Geographic variation of chlorinated pesticides, toxaphenes, and PCBs in human milk from sub-arctic and arctic locations in Russia. Sci Total Environ. 2003;306:179–195.
6. Siddiqui MKJ, Srivastava S, Srivastava SP, Mehrotra PK, Mathur N, Tandon I. Persistent chlorinated pesticides and intra-uterine foetal growth retardation: A possible association. Int Arch Occup Environ Health. 2003;76:75–80.
5. Ribas-Fito´ N, Sala M, Cardo E, Mazo¯n C, DeMuga ME, Verdu´ A, et al. Association of hexachlorobenzene and other organochlorine compounds with anthropometric measures at birth. Pediatr Res. 2002;52:163–167.
7. Torres-Arreola L, Berkowitz G, Torres-Sa´nchez L, Lo´pez-Cervantes M, Cebria´n ME, Uribe M, et al. Preterm birth in relation to maternal organochlorine serum levels. Ann Epidemiol. 2003;13:158–162.