Environmental Health Perspectives • volume 117 | number 12 | December 2009
4.7% respectively, compared with the previous year. Also in 2007,
China issued its first National Environment and Health Action Plan
(2007-2015) (Ministry of Health of China 2007). The plan addresses
the need to establish nationwide surveillance networks for environment
and health, and for different government agencies and stake holders
to share information and take responsibility. According to the action
plan, China will conduct national surveys to obtain accurate informa-
tion on the nature and extent of environmental pollution and its health
impact. China aims to form a comprehensive and efficient system for
environmental health by 2015. Furthermore, the Chinese government
will need to overcome policy and institutional barriers, such as lack of
effective legislation, mechanisms for interdepartmental coordination,
involvement of health authorities in environmental management, and
adequate staffing at the local level.
I thank B. Chen and S. Xu for their comments.
The author declares he has no competing financial interests.
Haidong Kan is from the School of Public Health, Fudan University.
His research interests include air pollution epidemiology, and health risk
Chen B, Hong C, Kan H. 2004. Exposures and health outcomes from outdoor air pollutants in
China. Toxicology 198(1-3):291–300.
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burden of disease due to outdoor air pollution. J Toxicol Environ Health A 68(13-14):1301–1307.
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In this issue of EHP, Braun et al. (2009) report that the concentration of
bisphenol A (BPA) in maternal urine from early pregnancy is associated
with female offspring having more externalizing behavior. Hyperactivity
and aggression are externalizing behaviors, and both are more frequent
in boys than in girls (HÖlling et al. 2008; Stene-Larsen et al. 2009).
Sexually dimorphic behaviors in female rodents have been shown to be
masculinized by exogenous estrogens (Ryan and Vandenbergh 2006),
and BPA is weakly estrogenic in most experimental systems (Kuiper
et al. 1998). Early pregnancy is the time in humans when masculinizing
hormones first have their effects on the human brain (Cohen-Bendahan
et al. 2005). I congratulate Braun and colleagues for bringing forth
epi demiologic data on a topic for which it is most welcome and timely.
Regulators at the U.S. Food and Drug Administration are currently
reconsidering policy on BPA (U.S. FDA 2009). Thus, interpretation of
the new results needs especially careful consideration.
Although the conclusions reached by Braun et al. (2009) may
appear to be supported by the experimental literature, the role of
estrogen in development—especially in the brain—is different in
rodents and primates (Witorsch 2002). Although plasma estrogens
increase in both rodents and primates during pregnancy, the increase
in humans (Burney et al. 2008) is > 3 times that in rodents (González
et al. 2003; Rodríguez-Cuenca et al. 2006); the absolute difference
in estrogen levels between species is even
greater (Witorsch 2002). More important,
in the developing male rodent brain, testos-
terone is converted to estrogen, and it is this
estrogen that is responsible for masculine
behavior (Li et al. 2008). In rodents, a mas-
culinizing effect of low-dose BPA has been
demonstrated (Chapin et al. 2008; Ryan
and Vandenbergh, 2006). In developing male primate brains, how-
ever, testosterone appears to masculinize directly without an estrogen
inter mediary (Li et al. 2008; Wallen and Hassett 2009). The syn-
thetic estrogen diethylstilbestrol, when administered during human
pregnancy, has no established effects on behavior of female offspring
(Cohen-Bendahan et al. 2005). According to Cohen-Bendahan
et al. (2005), “pre natal estrogen appears to have little effect on early
human development, perhaps because both males and females are
exposed to high levels of estrogen from the mother.” Furthermore, Li
et al. (2008) stated that “to the extent that endocrine disrupters such
as bisphenol A have been shown to duplicate or disrupt estradiol’s
action in the developing rodent nervous system …, the relevance of
such effects for human brain and behavioral development is called
Human Data on Bisphenol A and
Matthew P. Longnecker
BPA, however, could have effects on the developing human brain
that result from interaction with the androgen receptor (Sun et al.
2006) or that are due to interference with effects of estrogens on
neural circuitry or plasticity that are unrelated to sexual differentia-
tion (Leranth et al. 2008). However, it is unclear whether such effects
might occur at low BPA doses such as those to which humans are
exposed. Thus, with respect to an assessment of a biologically plausible
mechanism for Braun et al.’s findings of an association in human
females only (Braun et al. 2009), the literature is ambiguous and not
Although the sexual dimorphism of externalizing behavior is widely
recognized, absolute differences in externalized scores associated with
BPA cannot be determined using the sex-standardized data presented
(see Figure 1 in Braun et al. 2009). Thus, the size of the association
with BPA in girls cannot be compared with the size of the male–
female difference. Without this absolute difference (and corresponding
sex-specific data on distributions) for comparison, we cannot know
whether the largest estimated “effect” of BPA exposure is to produce
girls who behave like boys or girls who still behave like girls. Such a
close interpretation, before the results are confirmed by others, is per-
The most important information provided by Braun et al. (2009)
may be the correlation among urinary levels of BPA (on a creatinine
basis) at different times during pregnancy (≤ 0.11). This means that mea-
suring a single urine sample provides little information about longer-term
exposure. This is believable because labeled BPA has a half-life of hours
in humans (VÖlkel et al. 2002), and exposure appears to vary from day
to day (Nepomnaschy et al. 2009). If this degree of difficulty in charac-
terizing longer-term exposure in pregnancy is true in general of BPA,
epidemiologists face a challenge in finding true associations between
developmental exposure with outcomes, should any exist.
With the challenge in charac terizing exposure now more clear, the
exploration of other strategies may be a priority. For example, BPA can
form adducts with DNA in vivo (Atkinson and Roy 1995; Izzotti et al.
2009). Could adducts of BPA with albumin be detectable and be a
better biomarker of exposure in humans? Other, improved biomarkers
of exposure in humans are also conceivable, although they may be less
feasible in routine studies (Fernandez et al. 2007).
Vigilance regarding potential adverse effects of ubiquitous, low-level
exposures is a necessity of modern life. Braun et al. (2009) present a
complete analysis of data on a critical topic. This initial report, however,
may raise unrealistic expectations about what epidemiologic studies can
contribute on this topic. Their findings bring to mind Tufte’s Evidence
Decay Cycle: “too often the first published study testing a new treat-
ment provides the strongest evidence that will ever be found” (Tufte
2006). Given the potential implications of Braun et al.’s findings to
human health, let us hope that these findings will not be confirmed in
humans and that the best evidence of adverse effects of BPA will come
from toxicology studies.
The author declares he has no competing financial interests.
Matthew P. Longnecker
National Institute of Environmental Health Sciences
National Institutes of Health
Department of Health and Human Services
Research Triangle Park, North Carolina
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volume 117 | number 12 | December 2009 • Environmental Health Perspectives