Polybrominated Diphenyl Ethers and Cryptorchidism: Confounding or Cause and Effect
Environ Health Perspect. doi:10.1289/ehp.11052 available via http://dx.doi.org [Online 22 April 2008]
Referencing: Flame Retardants in Placenta and Breast Milk and Cryptorchidism in Newborn Boys
Main et al. (2007) reported that elevated levels of polybrominated diphenyl ethers (PBDEs) in breast milk, but not placenta, were associated with congenital cryptorchidism in Danish and Finnish boys. For the Danish cohort, the researchers used a case–cohort design in which biological samples were collected from all study participants, whereas for the Finnish cohort, they used a nested case–control design. The matching criteria used for Finnish mothers who gave birth to boys with cryptorchidism (measured at birth) and matched Finnish controls included the following: parity, smoking (yes/no), diabetes (yes/no), gestational age (± 7 days), and date of birth (± 14 days). However, Main et al. (2007) did not provide information on adjustments made to account for the type/severity of diabetes (Virtanen et al. 2006), smoking habits (Kurahashi et al. 2005), alcohol consumption (Damgaard et al. 2007), cesarean section (Hjertkvist et al. 1989; Kurahashi et al. 2005), and other factors that may be associated with cryptorchidism.
Interestingly, Main et al. did note that approximately 12% and 18% of breast milk samples and placentas, respectively, were obtained from diabetic Finnish mothers of cryptorchid boys, compared with 0% of controls (Main et al. 2007), but they conducted no further inquiry on this discrepancy. Damgaard et al. (2007) previously evaluated this same Danish–Finnish cohort and adjusted for confounders and effect modifiers for differences observed based on country, smoking, caffeine intake, alcohol consumption (including binge-drinking episodes), social class, maternal age, parity, maturity, and birth weight. Damgaard et al. (2007) noted an association between maternal alcohol consumption (≥ 5 drinks/week) and transient cryptorchidism. Despite these findings, Main et al. (2007) provided no information on stratified alcohol consumption or other potential confounders, such as caffeine intake or social class.
Main et al. (2007) concluded that an association exists between PBDE levels in breast milk and cryptorchidism in boys, but we should be cautious of this interpretation, given that Main et al. (2007) may not have adequately addressed potential confounders.
M.B. declares he has no competing financial interests. M.L.H. and T.S. work for Albemarle Corporation, a manufacturer of specialty chemicals, including brominated flame retardants.
Marek Banasik
Institute of Public Health and Environmental Protection
Warsaw, Poland
E-mail: iphep.banasik@gmail.com
Marcia L. Hardy
Todd Stedeford
Health, Safety & Environment
Albemarle Corporation
Baton Rouge, Louisiana
References
Damgaard IN, Jensen TK, Petersen JH, Skakkebæk NE, Toppari J, Main KM. 2007. Cryptorchidism and maternal alcohol consumption during pregnancy. Environ Health Perspect 115:272–277.
Hjertkvist M, Damber J-E, Bergh A. 1989. Cryptorchidism: a registry based study in Sweden on some factors of possible aetiological importance. J Epidemiol Community Health 43:324–329.
Kurahashi N, Kasai S, Shibata T, Kakizaki H, Nonomura K, Sata F, et al. 2005. Parental and neonatal risk factors for cryptorchidism. Med Sci Monit 11:CR274–283.
Main KM, Kiviranta H, Virtanen HE, Sundqvist E, Tuomisto JT, Tuomisto J, et al. 2007. Flame retardants in placenta and breast milk and cryptorchidism in newborn boys. Environ Health Perspect 115:1519–1526.
Virtanen HE, Tapanainen AE, Kaleva MM, Suomi A-M, Main KM, Skakkebaek NE, et al. 2006. Mild gestational diabetes as a risk factor for congenital cryptorchidism. J Clin Endocrinol Metab 91:4862–4865.
PBDEs and Cryptorchidism: Main et al. Respond
Environ Health Perspect. doi:10.1289/ehp.11052R available via http://dx.doi.org [Online 22 April 2008]
In their letter, Banasik et al. emphasize that the etiology of cryptorchidism may be multifactorial, and we agree. As stated in the "Discussion" of our article (Main et al. 2007), exposure to environmental chemicals is only one of many adverse factors that alone, or in combination with each other, may cause testicular maldescent. In turn, lifestyle factors such as smoking and drinking of alcohol may be interrelated, and a certain lifestyle may augment the risk of exposure to endocrine-disrupting chemicals. Genetic factors, complex medical syndromes, and lifestyle factors have been previously identified as risk factors for cryptorchidism, but a significant proportion of cryptorchidism cases still remains unexplained (Virtanen et al. 2007).
In our study (Main et al. 2007) we found an association between the level of polybrominated diphenyl ethers (PBDEs) in breast milk and congenital cryptorchidism. We reported that this remained significant after adjusting for other well-known risk factors for cryptorchidism, such as premature birth or low birth weight for gestational age (Main et al. 2007), as well as adjusting for maternal age, maternal prepregnancy body mass index, parity, and date of childbirth within the cohort, which may affect the level of compounds found in breast milk samples (Main et al. 2007). In the analysis of the entire Danish–Finnish binational cohort, other novel risk factors for cryptorchidism, such as regular maternal alcohol consumption during pregnancy and mild diabetes, were identified (Damgaard et al. 2007; (Virtanen et al. 2006).
Table 1.
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We originally decided against including additional confounders in our analysis (Main et al. 2007), considering the size of our study group and thus the low number of cases for each confounder, which induces a potential risk of both false-positive and false-negative results (Table 1). However, in a binary logistic regression analysis including all confounders, as suggested by Banasik et al., the association between the level of the seven most prevalent PBDEs (BDEs 28, 47, 66, 99, 100, 153, and 154) and congenital cryptorchidism remained significant (p < 0.039). Confounders included maternal age, maternal prepregnancy body mass index, gestational age, and weight for gestational age included as continuous variables; parity (1 vs. 2 vs. ≥ 3), country of origin (Denmark/Finland), social class (high- and low-grade professionals vs. skilled and unskilled workers vs. students and unemployed), smoking (yes/no), diabetes (yes/no), binge episodes (yes/no), and alcohol consumption (0 vs. 1–4 vs. ≥ 5 drinks/week) were entered as categorical factors, as described by Damgaard et al. (2007).
In conclusion, the association between perinatal exposure to PBDEs and congenital cryptorchidism was significant even after controlling for confounding factors. Our study could not determine whether a direct causal relationship exists or whether other factors contribute to our findings. Because the exposure to PBDEs is still considerable in some areas, our results should raise concern and stimulate further investigations of human populations.
The authors declare they have no competing financial interests.
Katharina M. Main
University Department of Growth and Reproduction
Copenhagen, Denmark
E-mail: katharina.main@rh.regionh.dk
Jorma Toppari
Departments of Physiology and Paediatrics
University of Turku
Turku, Finland
References
Damgaard IN, Jensen TK, the Nordic Cryptorchidism Study Group, Petersen JH, Skakkebæk NE, Toppari J, et al. 2007. Cryptorchidism and maternal alcohol consumption during pregnancy. Environ Health Perspect 115: 272–277.
Main KM, Kiviranta H, Virtanen HE, Sundqvist E, Tuomisto JT, Tuomisto J, et al. 2007. Flame retardants in placenta and breast milk and cryptorchidism in newborn boys. Environ Health Perspect 115:1519–1526.
Virtanen HE, Bjerknes R, Cortes D, Jørgensen N, Rajpert-De Meyts E, Thorsson AV, et al. 2007. Cryptorchidism: classification, prevalence and long term consequences. Acta Paediatr 96:611–616.
Virtanen HE, Tapanainen AE, Kaleva MM, Suomi AM, Main KM, Skakkebæk NE, et al. 2006. Mild gestational diabetes as a risk factor for congenital cryptorchidism. J Clin Endocrinol Metab 91:4862–4865.
