Components of Plastics Experimental Studies in Animals and Effects On Human Health

Components of Plastic: Experimental Studies in Animals and Relevance for Human
Health
Author(s): Chris E. Talsness, Anderson J. M. Andrade, Sergio N. Kuriyama, Julia A.
Taylor and Frederick S. vom Saal
Source: Philosophical Transactions: Biological Sciences , Jul. 27, 2009, Vol. 364, No. 1526,
Plastics, the Environment and Human Health (Jul. 27, 2009), pp. 2079-2096
Published by: Royal Society
Stable URL: http://www.jstor.com/stable/40485983
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PHILOSOPHICAL
TRANSACTIONS
- of - -n
THE ROYAL r< Phil. Trans. R. Soc. B (2009) 364, 2079-2096
SOCIETY JLF doi:10.1098/rstb.2008.0281
Review
Components of plastic: experimental studies in

animals and relevance for human health
Chris E. Talsness1*, Anderson J. M. Andrade2, Sergio N. Kuriyam
Julia A. Taylor4 and Frederick S. vom Saal4'
1 Department of Toxicology, Institute of Clinical Pharmacology and Toxicology, Charité University
Medical School Berlin, Campus Benjamin Franklin, Garystr. 5, Berlin 14195, Germany
Department of Physiology, Federal University of Paraná, Curitiba, Brazil
^Laboratory of Environmental Toxicology, National School of Public Health, Oswaldo Cruz Foundation
(FIOCRUZ), Rio de Janeiro, Brazil
4 [ Division of Biological Sciences, University of Missouri, Columbia, MO, USA
Components used in plastics, such as phthalates, bisphenol A (BPA), polybrominated dipheny

ethers (PBDE) and tetrabromobisphenol A (TBBPA), are detected in humans. In addition to
their utility in plastics, an inadvertent characteristic of these chemicals is the ability to alter the
endocrine system. Phthalates function as anti-androgens while the main action attributed to BPA
is oestrogen-like activity. PBDE and TBBPA have been shown to disrupt thyroid hormone homeo-
stasis while PBDEs also exhibit anti-androgen action. Experimental investigations in animals
indicate a wide variety of effects associated with exposure to these compounds, causing concern
regarding potential risk to human health. For example, the spectrum of effects following perinatal
exposure of male rats to phthalates has remarkable similarities to the testicular dysgenesis syndrome
in humans. Concentrations of BPA in the foetal mouse within the range of unconjugated BPA levels
observed in human foetal blood have produced effects in animal experiments. Finally, thyroid
hormones are essential for normal neurological development and reproductive function. Human
body burdens of these chemicals are detected with high prevalence, and concentrations in young
children, a group particularly sensitive to exogenous insults, are typically higher, indicating the
need to decrease exposure to these compounds.
Keywords: plastic; endocrine disruptor; phthalates; bisphenol A; polybrominated diphenyl ether;
tetrabromobisphenol A
1. INTRODUCTION binding to receptors and hormone transport proteins

Due to the high-volume generation of plastics and or by
lowaltering the metabolism or synthesis of endogen-
production costs, consumers typically use many plastic ous hormones, eventually influencing recruitment of
items only once before discarding them. Envir- transcription factors and altering gene expression in
onmental concerns associated with plastic use are cells (Wetherill et al. 2007). This is of particular con-
not only because of the amount of waste, but also cern for the developing organism, as it is sensitive to
the leaching of substances out of the plastic. Com- changes in the hormonal milieu, or drug or chemical
ponents used in plastics, such as bisphenol A (BPA), exposure, which can result in organizational changes
polybrominated diphenyl ethers (PBDE), tetrabromo- that are permanent (Guillette et al. 1995). This is in
bisphenol A (TBBPA) and phthalates, are released from contrast to the situation in adults where changes in
plastic products, and are also known as endocrine-steroid hormones often lead to activational changes
disrupting compounds (EDCs) owing to their ability that are transient. Epigenetic changes have been seen
to modulate the endocrine system. The detection of following early developmental exposure to EDCs in
EDCs in the environment, biota and humans is of animal studies, characterized by modified methylation
concern due to their potential to interfere with thepatterns of genes leading to altered gene expression
physiology of living organisms (see Oehlmann et al. 2009) .and phenotypic changes (Skinner & Anway 2007).
In general, EDCs may disrupt the endocrine system Human exposures to EDCs during this particularly
by competing with endogenous steroid hormone vulnerable developmental time frame have been docu-
mented in a number of studies showing contamination
of human breast milk (Norén & Meironyté 2000; Sun
* Author for correspondence (chris. talsness@charite.de). et al 2004; Main et al. 2006), foetal liver (Schecter
All authors contributed equally to this review. et al. 2007), amniotic fluid (Ikezuki et al 2002) and
One contribution of 15 to a Theme Issue 'Plastics, the environment cord blood (Schönfelder et al. 2002; Guvenius et al
and human health'. 2003). Data from animal and human studies suggest
2079 This journal is © 2009 The Royal Society

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2080 C. E. Talsness et al. Endocrine disruptors
that EDCs may play a role in the development of cancer et al 2006). Considering that developing organisms are
(Takashima et al 2008) , the reported decline in human particularly vulnerable to the effects induced by phtha-
sperm count (Mocarelli et al. 2008), temporal increases lates, newborns undergoing medical treatment in inten-
in the frequency of developmental abnormalities of the sive care units may be at increased risk when compared
male reproductive tract (Sharpe & Skakkebaek 2008) with the general population. In a pilot study conducted
and the trend towards precocious puberty in human by Koch et al (2006), the daily DEHP intake of 45 neo-
females (Schoeters et al. 2008). nates who were treated with various medical procedures
Phthalates function as plasticizers to give flexibility was calculated. The median and 95th percentile was
to high-molecular-weight polymers and are found in 0.042 and 1.780 mg DEHP (kgbw"1) d ~' respectively,
soft plastic products (the addition of phthalates and the maximum calculated intake was 2.3 mg
makes brittle polyvinyl chloride (PVC) soft). In DEHP (kgbw"1) d"1.
addition, phthalates are also used as chemical additives
in gel capsules, cosmetics and other personal-care pro-
ducts. Bisphenol A is widely used in the production of(b) Experimental studies
epoxy resins, polycarbonate plastics and brominatedAlthough phthalates display low general toxicity,
flame retardants (BFRs). BPA is the monomer (as exposure to certain compounds is associated with dis-
opposed to an additive) used for production of poly-ruption of endocrine and reproductive functions in
carbonate plastic intended for food and beverage experimental animals. The male reproductive tract
contact and many other products; it is also used to seems to be particularly sensitive to phthalate exposure.
make resins that line metal food and beverage cans. Treatment of adult male rats with high doses of certain
TBBPA and PBDEs make up approximately 59 and phthalates (e.g. 2000 mg DEHP kg" M"1) results in
33 per cent of the world market of BFRs (Law et al. rapid and severe changes in the testis (Gray &
2006), respectively, and are incorporated in a wide Gangolli 1986; Dostal etal 1988). The observed altera-
variety of materials including plastics intended for elec- tions in spermatogenesis are thought to result from dys-
tronics and appliances as well as fabrics. function in Sertoli cells, which cannot adequately
This review will present some aspects of human provide physical and metabolic support to germ cells
exposure to these compounds and investigations de- (Gray & Gangolli 1986). There is also experimental evi-
scribing effects in animal models. The potential fordence showing that phthalates can target the Leydig
human health effects based on evidence derived from cells and induce multiple hormonal disturbances
(Akingbemi et al 2004; Lin et al 2008). However,
experimental studies in animals will be discussed for
each of these chemicals. most reproductive effects are not exerted by phthalate
diesters themselves but rather by their active primary
monoester metabolites formed in the liver, which are
2. PHTHALATES considered the proximate toxicants (Gray & Gangolli
(a) Human exposure 1986). Recent evidence suggests that phthalates can
Phthalate esters have recently attracted the specialalso at- induce adverse responses in females following
tention of the scientific community, regulatory agencies pre- and post-natal exposure (Grande et al 2006,
2007; Gray et al 2006).
and the general public as a consequence of their high pro-
duction volume, widespread use as plasticizers and Although most reproductive effects have been
chemical additives and possible endocrine-related effectsdescribed in rats, phthalates can induce testicular
(Mylchreest et al. 1999). Phthalates can easily leach injury
out in several other species including mice (Lamb
of products to contaminate the external environment et al. 1987), guinea pigs (Gray et al 1982) and ferrets
because they are not chemically bound to the plastic (Lake et al 1976). However, some species, such as
matrix or to other chemicals in formulations. Di-(2- hamsters and non-human primates, seem to be less
ethylhexyl) phthalate (DEHP) is the most commonly sensitive than rats (Gray et al 1982; Foster et al.
used phthalate plasticizer for PVC (Matsumoto et 1983; al. Kurata et al. 1998), and part of this variability
2002), but other compounds such as di-butyl phthalate may be attributed to differences in phthalate bioavail-
(DBP), used as a fixative in cosmetics and other formu- ability (Foster et al 1983; Ito et al 2005). Accordingly,
lations, are also a cause of concern. Recent biomonitor- it has been argued that humans and non-human pri-
ing studies in the USA and Europe have detected mates are less susceptible to the effects of phthalates,
relatively high levels of monoester metabolites of phtha-owing to the lower conversion of parent compounds
lates in the urine of the general population (Koch et into
al active monoester metabolites (Mckee et al.
2004, 2006; Silva et al 2004). In a recent study (Koch 2004). In a study by Kurata et al (1998), no changes
et al 2006), the estimated median and 95th percentile in testis weight or histopathology were observed in
of daily DEHP intake for a German population (n adult = marmosets administered orally at 100, 500 or
85) was 5.6 and 21 juug (kgbw"1) d"1, respectively. 2500 For mg DEHP kg^d"1 for 13 weeks. More recently,
children aged 3-14 years, these values were significantlythe absence of testicular effects was also reported in
higher- 7.7 and 25 'xg (kgbw"1) d"1 (n = 254). Other young adult cynomolgus monkeys and juvenile mar-
studies have confirmed these data (reviewed by mosets exposed to high DEHP doses (500-
Heudorf et al 2007). In addition, critically ill patients2500 mg kg"1 d"1) (Pugh et al 2000; Tomonari et al
and neonates hospitalized in intensive care units may 2006). However, non-human primates have not been
be exposed to significantly higher doses of phthalatesextensively evaluated during foetal and neonatal
that migrate from medical devices such as blood bags,periods, which represent developmental windows
catheters and nasogastric and intravenous tubes (Kochespecially susceptible to exogenous insults. A recent
Phil Trans. R. Soc. B (2009)

31.125.186.252 on Tue, 14 Nov 2023 19:46:37 +00:00
Endocrine disruptors C. E. Talsness et al. 2081
work by Hallmark et al (2007) indicates that neonatal Sertoli cell-only (SCO) tubules, Leydig cell aggregates
marmosets treated orally with SOOmgkg1 d"1 DBP and multinucleated giant germ cells (Gray et al. 2000;
respond similarly to rats in relation to changes in Fisher et al 2003; Andrade et al 2006Ò). Reductions
testosterone production and Leydig cell alterations, in Sertoli cell number and/or proliferation have also
although marmosets seem to be able to reverse the been reported in neonatal rats treated with phthalates
suppression of testosterone production more effi- (Dostal et al 1988; Li et al 2000). However, this
ciently than rats. Due to the lack of data on in utero appears to be a transient effect, as no changes in the
and early post-natal exposures, it is not possible to number of Sertoli cells are observed later in life
draw conclusions regarding possible developmental (Dostal et al 1988; Andrade et al. 20066).
effects in non-human primates. In both adult and developing males, disturbance
In fact, the main concern involving phthalates is Leydig and Sertoli cell functions constitutes integr
related to the effects induced during pre- and early effects of phthalates. In addition, gene profiling d
post-natal development. Recent animal toxicity studies obtained by microarray analysis indicate that phth
indicate that exposure to certain phthalates results in lates affect similar genetic targets in pre-pubertal
severe disorders in the developing male reproductive foetal rat testes (Lahousse et al 2006). However, hor
system, including defects in the external genitalia, monal and local cell signalling perturbations durin
undescended testes and testicular lesions. Reproductive early development may irreversibly alter reproduct
toxicity induced during the perinatal period was reported and endocrine functions in a manner that may not
for DEHP (Gray et al. 2000; Andrade et al. 2006a), be predicted from post-natal exposure. In addition
DBP (Mylchreest et al. 1999), butyl benzyl phthalate although several target genes involved in the devel
(Gray et al 2000; Nagao et al. 2000) and, to a lesser ment and function of foetal Leydig and Sertoli ce
extent, for diisononyl phthalate (Gray et al. 2000). have been identified so far (Shultz et al 2001;
Male rat offspring exposed in utero or both in utero and Lehmann et al 2004), the mechanisms by which
during lactation to high phthalate doses (e.g. 500 mg phthalates alter the expression of these genes are
DBP kg"1«!"1) display reproductive tract abnormalities currently unknown.
compatible with disruption of androgen-dependent
development and impaired testicular function
(Mylchreest et al. 1999; Gray et al. 2000; Andrade et al. (c) Relevance of phthalate effects for humans
2006a). The phenotypic alterations manifested in Interestingly, the spectrum of effects obtained following
male offspring include cryptorchidism, hypospadias, perinatal exposure of male rats to phthalates has
atrophy or agenesis of sex accessory organs, testicular remarkable similarities with the human testicular dys-
lesions (e.g. small fluid-filled testes), reduced daily genesis syndrome (TDS). According to Skakkebaek
sperm production, delayed preputial separation, per- et al (2001), the human TDS is characterized by low
manent retention of nipples and decreased (feminized) sperm counts, cryptorchidism, hypospadias and tes-
anogenital distance. ticular cancer, and the clinical expression of these
Unlike other anti-androgens, which act by binding to symptoms may vary with the severity of the syndrome.
the androgen receptor and thus inhibit its ability to Accordingly, less severe manifestations would result in
respond to androgens, phthalates disrupt the develop- impaired spermatogenesis while other symptoms such
ment of androgen-dependent structures mainly by inhi- as testicular cancer may be present in more severely
biting foetal testicular testosterone biosynthesis (Parks affected individuals (Skakkebaek et al 2001). Similar
et al 2000; Wilson et al 2004; Howdeshell et al to the human TDS, the effects induced by phthalates
2008). This effect is mediated by changes in gene in rats constitute a continuum of response with the
expression of enzymes and proteins involved in testos- most severe manifestations and highest incidence of
terone production by foetal Leydig cells, including thereproductive tract malformations observed at high
steroidogenic acute regulatory (StAR) protein, which doses (Foster 2006). In utero exposure of rats to active
participates in the transport of cholesterol to the inner phthalates such as DEHP and DBP has been suggested
mitochondrial membrane, the step in the steroidogenicas a useful animal model for human TDS, as in both
pathway that is considered to be rate-limiting (Shultz humans and rodents disturbance of foetal Leydig and
et al 2001; Lehmann et al 2004). Recently, the Sertoli cell functions plays a major role in induction
expression of another product of the foetal Leydig of TDS-like symptoms (Fisher et al 2003).
cell, insulin-like factor 3 (InsB), has been shown to However, the main question involving phthalates is
be reduced in phthalate-exposed animals (Wilsonwhether the level of human exposure is sufficient to
et al 2004). Such an effect might explain the incidence adversely impact male and/or female reproductive
of retention of testes in the abdomen (cryptorchidism)health. A study by Swan et al. (2005) reported an
association between phthalate exposure and reduced
following phthalate exposure, as Insl3 is involved in
the initial stages of testicular descent into the scrotumanogenital distance in human infants, an effect that
(Wilson et al 2004; Foster 2006). is also observed in rats. However, the range of doses
Testicular histopathology resulting from phthalate typically used in animal studies is three to four
orders of magnitude greater than the estimated daily
exposure is seen early in the foetal testis with the pres-
ence of dysgenetic areas characterized by malformed exposure of humans. Only recently have researchers
seminiferous cords containing multinucleated gono- begun to investigate and report on possible biological
cytes and aggregates of Leydig cells (Barlow & Foster changes at doses within the range of median human
2003; Fisher et al 2003). In adult offspring, affected phthalate exposure (Lehmann et al. 2004; Andrade
testes display reduced germ cell differentiation, et al 2006c; Lin et al 2008).
Phil. Trans. R. Soc. B (2009)

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Some studies indicate that treatment of rat dams related drug diethylstilbestrol (DES) was described
with active phthalates may result in non-monotonic (Dodds et al. 1938). In the 1950s, polymer chemists
(biphasic) dose-responses for the activity/expression discovered that BPA molecules could be polymerized
of enzymes and proteins involved in the biosynthesis to make polycarbonate plastic. Bisphenol A is also
of steroid hormones in the offspring. Lehmannthe et base
al. compound used in the manufacture of the
resin lining of food and beverage cans in the USA
(2004) studied alterations in genes coding for steroido-
genic enzymes in the foetal testis of rats exposed to other countries, although the Japanese can
and many
DBP. In this study, the authors reported reductions industry changed the formulation of the plastic lining
in several genes at doses that approach maximum of cans in the late- 1990s. This voluntary action was
human exposure levels. In a recent study with DEHP, reported to be associated with a loss of the previous
Andrade et al. (2006c) have shown a striking biphasic correlation between use of canned drinks and urine
dose- response for aromatase enzyme activity in the levels of BPA in Japanese students as well as over a
brain of neonatal males, with low-dose inhibition and 50 per cent decrease in BPA levels (Matsumoto et al.
high-dose stimulation. Since aromatase is a key 2003). These latter findings suggest that use of BPA-
enzyme in the biosynthesis of oestrogens, phthalatebased resins to line cans contributes significantly to
exposure might be associated with disturbances of the the human body burden of BPA. Food contact items
normal balance between androgens and oestrogens. (can lining, food packaging and food and beverage
In addition to studies using low phthalate doses, containers) are thought to be the major contributors
recent studies have been conducted in order to evalu- to the median and mean values of approximately
2-4ngml~1 of unconjugated BPA detected in adult
ate the possibility of cumulative effects, since humans
are exposed to multiple phthalates that are known and foetal serum (Vandenberg et al. 2007). Pure
to affect male reproductive development in rats. water was poured into food cans that had contained
Howdeshell et al. (2007, 2008) demonstrated that different products and a polycarbonate food storage
different phthalates can act in a cumulative, dose- container. The products were heated to 100°C for
additive manner to reduce the testicular testosterone 24 h, and BPA was analysed by HPLC with
production by the rat foetal testis. Rider et al. (2008)
CoulArraay detection. The data presented in figure 1
reported dose-additive responses on reproductive mal- reveal that all products leached detectable levels of
formations and androgen-dependent organ weights BPA, although there were differences in the amount
with developmental exposure to a seven-chemical of leaching from different manufacturers' products.
anti-androgenic mixture that included some active As expected, the cans that had contained the acidic
phthalates. Coadministration of no-effect doses of tomato sauce resulted in the highest BPA values,
DEHP and DBP reduces testicular testosterone since acid accelerates hydrolysis of the ester bond link-
levels and results in misshapen seminiferous cords
ing BPA molecules in polycarbonate and resins.
and gonocyte multinucleation in the rat foetal testis
Another common use for BPA is as the monomer in
(Martino-Andrade et al 2008). dental sealants and composites used for fillings, from
which BPA leaches in variable amounts and for different
(d) Conclusions lengths of time depending on the product ( Joskow et al.

Overall, the resemblance of phthalate effects in rats to 2006). BPA is also an additive (referred to as a plasti-
human reproductive disorders has raised concerns cizer) in PVC plastic products. For example, BPA has
over a possible link between phthalate exposure andbeen reported to be present in PVC products such as
human disease, even though most reproductive tract stretch film (Lopez-Cervantes & Paseiro-Losada
abnormalities in animal studies have been reported at2003). It is also used in printer ink and to coat paper
dosages that probably result in internal dose concen-used for receipts (referred to as 'carbonless paper'). It
trations that are well above those observed in humans. is thus a major contaminant in recycled paper products
However, recent evidence for effects at lower doses as (Vandenberg et al. 2007). Polycarbonate food storage
well as the results of combined toxicity studies andand beverage containers (the hard, clear containers,
some epidemiological data on possible associationswhich may be tinted in the case of sport water bottles
or baby bottles) cause concern regarding their potential
between phthalate exposure and reproductive effects
in humans have provided further evidence for concern.to leach BPA because they are re-usable (Nerin et al.
2003), and repeated use leads to an increase in leaching
The investigation of phthalate effects in non-human pri-
mates during pre- and early post-natal periods, the(Brede et al. 2003). Many of these containers are mar-
possibility of cumulative effects at low doses and aketed for use in the microwave, despite the fact that
better understanding of the mode of action of phtha-heating is known to increase BPA leaching levels. It is
lates and its relevance to humans are critical issues a basic characteristic of the ester bond linking BPA mol-
ecules together in polycarbonate plastic and resins that
that should be addressed in future experimental studies.
the rate of breaking of the bond by hydrolysis increases
with heat, releasing free BPA (Bae et al. 2002), and an
3. BISPHENOL A increase in leaching also occurs as a result of either an
(a) Sources and amounts of human increase or decrease in pH (Welshons et al. 2006;
BPA exposure Vandenberg et al. 2007). When food or liquids (such
Bisphenol A was reported to be a synthetic oestro- as beer) are placed into a can, they are heated to a
gen (relative potency was not assessed) in 1936 high temperature for sterilization. The consequence is
(Dodds & Lawson 1936), 2 years before the oestro- that food and beverages in cans have variable levels of
genic activity of the structurally and functionally BPA based on whether the contents are lipophilic
Phil. Trans. R. Soe. B (2009)

31.125.186.252 on Tue, 14 Nov 2023 19:46:37 +00:00
consistent with reports of blood levels of unconjugated

BPA in people from other countries such as Japan
(Vandenberg et al. 2007). In this review of the pub-
lished literature, the authors determined that blood
levels in humans identified by numerous analytical
methods consistently showed approximately 10-fold
higher median or mean levels of unconjugated BPA
than average blood levels found throughout a 24 h
period after laboratory rats were administered a BPA
dose equal to the tolerable daily intake (TDI). The
TDI corresponds to the amount of a chemical a
person can be exposed to on a daily basis over an
extended period of time (usually a lifetime) without
Figure 1 . Bisphenol A (BPA) concentration in water placed suffering deleterious effects; this is also referred to by
into food cans that had contained different products. Two US regulatory agencies as the 'reference dose' and
or three different brands of each product were examined. 'acceptable daily intake dose'.
The cans were emptied, cleaned and rinsed with water that Currently, a dose of 50 ixgkg"1 d"1 is considered
did not contain detectable levels of BPA. The 1 0 cans and
'safe' for daily human consumption by the US
a single new reusable 'microwave safe' polycarbonate food
Environmental Protection Agency (EPA) (IRIS
container were filled with HPLC-grade water and heated to
1988) and Food and Drug Administration (FDA).
100°C for 24 h. Bisphenol A was extracted and analysed by
Findings reported by Vandenberg et al. (2007) led to
HPLC with CoulArray detection (limit of detection was
0.01 ppb). Negative controls in glass bottles gave undetect-
a consensus conclusion by 38 scientists who attended
able levels of BPA. Spiked samples in glass containers gave a US National Institutes of Health (NIH) sponsored
>95 per cent recovery. Significant leaching of BPA occurred conference on BPA (vom Saal et al. 2007) that current
from each type of product tested. levels of human exposure to BPA already exceed the
presumed safe daily exposure dose. The data pre-
sented in the review indicate that: (i) BPA is detected
at the nanogram per millilitre (ppb) levels; (ii) uncon-
and/or acidic or alkaline (figure 1), all of which increase jugated (bioactive) BPA is found in blood and (iii) the
leaching (see the Environmental Working Group web- same levels are found in its conjugated (glucuroni-
site for additional data on leaching of BPA from cans, dated or sulphated) form in urine (Vandenberg et al.
at www. EWG. org) . 2007). This is in sharp contrast to a review that con-
A critical issue regarding routes of exposure to BPA cluded that BPA is rapidly and completely cleared
was revealed by the Canadian Ministry of the from the blood of adults following oral absorption
Environment, which determined that BPA poses a(Willhite et al. 2008). The conclusion that all ingested
threat to aquatic wildlife at current levels at which BPAit is immediately metabolized (conjugated) to bio-
is found in aquatic ecosystems (Canada 2008). Thislogically inactive metabolites is thus not consistent
government report and other reviews (Vandenberg with the published literature. The 'back calculation'
et al. 2007) identify that a number of studies show approach of estimating human exposure to BPA
that BPA is leaching out of products being thrown based on the assumption that all orally absorbed
into landfills and getting into ground water, contami- BPA is immediately cleared from blood into urine is
nating rivers, streams and drinking water. Whileanininvalid approach if the chemical is not immediately
an aerobic environment, BPA has a half-life of days, and completely metabolized (Barr et al. 2005).
has a greater density than water and thus ends up inBPA is one of the highest production volume chemi-
the sediment. In an anaerobic environment, BPA cals in commerce, with over 6 billion pounds produced
does not degrade. The Canadian Government is thusin 2003 (Burridge 2003), and a significant increase in
taking a regulatory approach to this problem that production volume was expected at that time. In order
involves not only trying to limit the use of BPA in to accurately estimate human exposure to BPA, we
food and beverage containers, but also involves would need to know what products it is used in,
trying to deal with the problem of disposal of BPA- since without this knowledge we have no way to deter-
containing plastic that cannot be recycled to producemine the potential for different routes of exposure.
new BPA-based products. This is currently not possible as identification of the
The US Centers for Disease Control and chemicals used in products, such as baby toys, food
Prevention (CDC) has measured BPA in the urine of and beverage containers or paper products, is not
people in the USA as part of the last national health required. The latter is interesting in that printer ink
survey (Calafat et al. 2008). The CDC reported that contains BPA, and the 'carbonless paper' used to pro-
93 per cent of people had detectable levels of BPA in vide receipts for purchases is coated with BPA (the
their urine. Interestingly, the median and mean levels BPA reacts with dye in the paper in response to
of unconjugated (parent) BPA reported in blood, as pressure or heat). Newspapers and carbonless paper
well as the lower and upper range reported for could be significant sources of transdermal BPA
women and their foetuses at the time of parturition exposure, and all recycled paper has BPA in it from
in Germany (Schönfelder et al. 2002), were virtuallythese sources (Vandenberg et al. 2007). Dermal
identical to values reported for total BPA in urine byabsorption of BPA from these potential sources of
the CDC. The findings by Schönfelder et al. are exposure has not been investigated.

31.125.186.252 on Tue, 14 Nov 2023 19:46:37 +00:00
2084 C. E. Talsness et al Endocrine disruptors
(b) Adverse health effects of BPA in decrease in maternal behaviour in mice (Palanza et al
laboratory animals 2002) and disruption of hippocampal synapses, leading
There were three reports released in 2007 and 2008 to the appearance of a brain typical of that seen in sen-
in North America: two from the USA and one ility in both rats and monkeys (MacLusky et al 2005;
from Canada (discussed subsequently). The first Leranth et al 2007, 2008).
was released as a consensus statement from an NIH- Related to the fact that type 2 diabetes is increas-
sponsored conference on BEA (vom Saal et al 2007). ing in many regions of the world is the finding
This document was co-authored by 38 scientists that whoexposure of adult mice to a low oral dose of
are experts in the field of endocrine disruption, and BPAthe(10 iJLgkg1 d"1) resulted in stimulation of in-
sulin secretion that was mediated by oestrogen
majority of scientists at this conference had conducted
research on BPA. The consensus document was a sum- receptor (ER) alpha, occurring as a rapid response
mediated by the extracellular signal-regulated kinases
mary of the findings in five accompanying review articles
1 and
that covered the entire published literature relating to the 2 (ERK1/2) pathway; and that the prolonged
health effects of BPA as of the end of 2006 (Crain et
hypersécrétion
al of insulin was followed by insulin resist-
2007; Keri et al 2007; Richter et al 2007<z,¿>; ance and postprandial hyperinsulinaemia (Alonso-
Vandenberg et al 2007; Wetherill et al 2007). Magdalena et al 2005, 2008; Ropero et al 2008).
The fact that these very-low-dose studies of BPA are
confirmed in cell culture studies that reveal molecular
(i) Adult exposure, experimental findings and pathways that mediate effects of BPA in the low parts
relevance for human health per trillion range has been reviewed (Wetherill et al
There is extensive published literature showing2007). the A consensus conclusion from the NIH-
effects of acute exposure to very low doses of BPA sponsored
in meeting on BPA was that the more recently
adult experimental animals: rats, mice and various discovered rapid-response pathway (as opposed to the
aquatic species (Richter et al 2007 a,b). However,nuclear an ERs acting as ligand-activated transcription
issue that has generated much confusion is the factors) rate may mediate many, but not all, of the low-
at which BPA is metabolized. As described earlier,dose if effects of BPA (vom Saal et al 2007).
one makes the assumption that virtually all BPA The prediction from mechanistic studies in mice
exposure is via an oral route and that virtually all concerning the molecular pathways by which very
BPA is immediately conjugated in the liver after low doses of BPA stimulate insulin production and
absorption from the gut (transported from the gut to secretion, which is then followed by insulin resistance
the liver via the direct hepatic portal vessels), then of (Ropero et al 2008), leads to the fact that BPA may
course there would be no concern about BPA posing be related to elevated blood insulin and glucose, as
a threat to adults. However, this assumption is not well as insulin resistance. In addition, Hugo et al
consistent with the published biomonitoring literature (2008) reported that human adipocytes removed
regarding levels of unconjugated BPA in human blood from different regions showed a marked suppression of
(Vandenberg et al 2007). Importantly, no rodent or the critical regulatory cytokine adiponectin, with the
human experiment has been conducted that involves maximum response occurring at 1 nM (0.23 ppb),
chronic exposure, although the human biomonitoring directly in the range of human exposure to BPA. A
data suggest virtual continuous exposure (Calafat decrease in adiponectin is related to an increased risk
et al 2008). This is a major gap that needs to be filled. for type 2 diabetes and cardiovascular disease and
The issue of route of exposure to BPA has generated heart attack (Beltowski et al 2008). It is thus of con-
significant controversy, since the default assumption is siderable interest that Lang et al (2008) reported
that oral exposure accounts for most (or virtually all) that in an analysis of data from 1455 people examined
BPA exposure in humans. It is well known that expo- for BPA levels in urine as part of the US National
sure to BPA via injection, which does not result in the Health and Nutrition Examination Survey
first-pass liver metabolism (glucuronidation/sulphation) (NHANES) conducted in 2003-2004, they found
that would occur following oral exposure, results in significant relationship between urine levels of BP
about a 10-20-fold higher amount of BPA in the and cardiovascular disease, type 2 diabetes and
blood relative to levels following oral administration abnormalities in liver enzymes. This report, suggesting
(Vandenberg et al 2007). However, if BPA is injected links between BPA and some of the most significant
into rodents at doses of BPA that are thousands of and economically burdensome human diseases, is
times lower than the lowest adverse effect level based on a cross-sectional study and therefore cannot
establish causality, but the fact that these findings are
(LOAEL) of 50 mg kg"1 d"1 that was used to establish
the safe dose of 50 |mg kg"1 d"1, it is logical to assume related to other studies that identify plausible mechan-
that findings from studies that used injection as the isms by which BPA at current levels of human
route of administration are also relevant to assessingexposure could result in these diseases greatly
the potential health hazards posed by BPA, while recog-strengthens the importance of the findings (vom Saal
nizing that a correction for differences in pharmaco- & Myers 2008).
kinetics based on route of administration is required.
Just a few examples of effects of low doses of BPA in
adult rodents are a significant stimulation of insulin (ii) Developmental exposure, experimental findings
secretion followed by insulin resistance in miceand relevance for human health
The greatest concern regarding exposure to BPA is
(Ropero et al 2008), a significant decrease in daily
sperm production in rats (Sakaue et al 2001), duringa development: foetuses, neonates, infants,

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Endocrine disruptors C. E. Talsness et al 2085
children and adolescents. The laboratory animal Table 1. Prenatal-neonatal exposure of mice and rats to
research on BPA is unique in that there are now hun-BPA at human exposure levels in relation to human health
dreds of studies that have examined doses of BPA trends.
within the range of human exposure rather than the

effects in mice and rats human health trends
more typical approach in regulatory toxicology of
only testing a few doses that are typically thousands
prostate hyperplasia and prostate cancer increase
of times higher than human exposure levels. The sur-
cancer
prise associated with the first 'low dose' publication mammary onhyperplasia and breast cancer increase
the effects of BPA in laboratory mice in 1997cancer (Nagel
et al 1997) was that effects on the reproductive abnormal urethra/ hypospadias
system in male offspring were found at a daily oral obstruction
dose to pregnant mice that was 25 000 times lower sperm count decrease sperm count decrease
than had ever been examined, and 25 times below early puberty in females early sexual maturation
the still current safe daily exposure dose according toovarian cysts/uterine polycystic ovary syndrome/
fibroids uterine fibroids
the US FDA and US EPA, as well as the European
abnormal oocyte miscarriage
Food Safety Authority (EFSA 2006). The lowest dose chromosomes
of BPA that had previously been examined was
body weight increase obesity increase
50mgkg~1d~1 in some traditional very-high-doseinsulin resistance type 2 diabetes
toxicological studies conducted in the 1980s. The hyperactivity/impaired attention deficit
50mgkg~1d~1 was thus the LOAEL, and this learning hyperactivity disorder
dose was divided by 10 to 'estimate' the no observable
adverse effect level (NOAEL) and divided by 1000 for
the EPA to estimate that 50 jxgkg^d"1 was safe for
daily human exposure (IRIS 1988). Numerous reviews (Soto et al 2008) and male reproductive organs in
have been published discussing the assumptions used in female rats and mice. Findings include chromosomal
estimating safe exposure levels for endocrine-disrupting abnormalities in oocytes in females (Susiarjo et al
chemicals such as BPA (vom Saal & Sheehan 1998; 2007), and long-term effects on accessory reproduc-
Markey et al 2003; Welshons et al 2003, 2006; vom tive organs that are not observed until mid-life, such
Saal & Hughes 2005; Myers & vom Saal 2008). as uterine fibroids and para-ovarian cysts (Newbold
One of the main concerns with the adverse effects et al 2007). Other studies have shown that very low
reported in response to developmental exposure to doses of BPA during pre-natal or neonatal develop-
very low doses of BPA (that produce blood levels ment in can result in permanent effects in male rats
animals below those in humans) is that they all relate and mice. Low doses of BPA cause a decrease in
to disease trends in humans (table 1). For example,daily sperm production and an increase in pros
there is an obesity epidemic in many regions of the size (vom Saal et al 1998), an increase in prostatic
world, and developmental exposure to BPA increases androgen receptors (Gupta 2000; Richter et al
body weight later in life (Howdeshell et al 1999; 2007<z,¿>) and a progression from hyperplasia of pros-
Takai et al 2000; Rubin et al 2001). In addition, neo- tate basal (stem) cells in the primary prostatic ducts
natal exposure to a low dose of DES (1 |xg kg"1 d"1) during foetal life (Timms et al 2005) to basal cell
stimulated a subsequent increase in body weight and squamous metaplasia in adulthood (Ogura et al
fat in CD-I mice, while a dose 1000 times higher 2007) and eventually to early stage prostate cancer
resulted in a significant decrease in body weight (prostatic interepithelial neoplasia or PIN) in response
(Newbold et al 2004). to adult administration of testosterone and oestradiol
Relevance for human health. The largest literature on (Ho et al 2006).
the adverse effects of BPA exposure during develop-
ment concerns adverse effects on brain structure,
chemistry and behaviour (Richter et al 2007 a>b). (c) Conclusions
One of the most interesting aspects of this literature The required testing of chemicals for regulatory pur-
is that there is a consistent finding of a loss of sex poses is not aimed at understanding molecular mech-
differences in brain structure, chemistry and behaviouranisms and focuses on effects occurring at high doses
owing to foetal/neonatal exposure to low doses of BPA. that are typically not relevant for human exposure
BPA thus appears to interfere with the normal pro- scenarios. Over the last 10 years, there has been a dra-
cesses that govern sexual differentiation, with brain matic shift in the approach of scientists with regard to
changes reported in both males and females, depend- investigating doses that are relevant for human
ing on the outcome measured (Fujimoto et al 2006; exposure to study the effect of BPA in laboratory ani-
Rubin et al. 2006; Palanza et al 2008). The impli- mals. This has led to a totally unique toxicological lit-
cations at the population level for disruption of erature revealing extensive evidence that effects in
normal socio-sexual behaviours have not been exten- laboratory animals are occurring at blood levels that
sively studied, although there are reports of changesare lower than those found in the average person in a
in play behaviour (Dessi-Fulgheri et al 2002) as welldeveloped country. This is clearly of great concern
as other socio-sexual behaviours (Farabollini et al for possible impact on human health.
2002) that could impact population dynamics. The assumptions used in chemical risk assessments,
There are also numerous studies of the effects of such as all dose -response curves are monotonie, and
low doses of BPA on the development of the female there is a threshold dose below which no effect

31.125.186.252 on Tue, 14 Nov 2023 19:46:37 +00:00
occurs at which the system is 'off, clearly do not apply congeners and TBBPA over the period 1977-1999.
to endogenous hormones, hormonally active drugs or The concentrations for different age groups were rela-
hormonally active chemicals. How can there be a tively similar, except for the 0-4 year olds who had
threshold at which no oestrogen responses occur for 1.6-3.5 times higher serum concentrations
a chemical that is adding oestrogenic activity to a (Thomsen et al. 2002b).
system that is already 'on' at zero dose of the exo-
genous chemical (Sheehan et al. 1999; Sheehan (c) Experimental studies on TBBPA
2005)? Also, all hormones show responses that are non- There are only a few published studies regarding the
monotonic, and non-monotonic dose -response curves toxicology of TBBPA. Information regarding the
have been reported in many BPA studies (Richter endocrine-disrupting potential of TBBPA mainly
et al. 2001 aM Alonso-Magdalena et al. 2008). The comes from in vitro studies and in vivo studies per-
need to integrate concepts of endocrinology in the formed in quail, fish and tadpoles; however, two
assumptions underlying chemical risk assessments papers describing a study in the rodent model have
will some day result in the development of a new system, been recently published.
and the data from findings with low doses of BPA
will play an important role in this paradigm shift
(i) Thyroid hormone effects
(Myers & vom Saal 2008).
An increase in thyronine (T3) in female rat offspring
and a reduction in circulating total thyroxine (T4)
4. BROMINATED FLAME RETARDANTS were observed in both sexes in a reproductive study
(a) Uses of TBBPA with exposure to TBBPA in food, beginning 70 or 14
Brominated flame retardants function by increasing days prior to mating of F0 males and females, respect-
the time between ignition of a fire and flash over, ively, and which continued throughout gestation and
which is the point when enough heat is generated to lactation up to 14 weeks of age at necropsy (Van der
cause combustion of flammable materials. TBBPA is Ven et al. 2008). Thyroid hormone concentrations
the classical halogenated flame retardant chemically were similarly altered at 1 2 weeks of age in a subacute
bonded to epoxy and polycarbonate resins. It is toxicity study (28 days of repeated dosing of TBBPA)
present in printed circuit boards and casings used in with a significant decrease in T4 and increase in T3 in
personal computers, printers, fax machines and cop- males. Parallel changes were observed in females; how-
iers. Dimethyl TBBPA is added to acrylonitrile- ever, they were not statistically significant (Van der Ven
butadiene-styrene (ABS) resin and high impact et al. 2008). In the same reproductive experiment,
polystyrene (HIP). This derivative is blended with the appraisal of brainstem auditory evoked potentials
polymers, meaning that it exists free in the chemical (BAEP), a means to detect effects on hearing, indi-
matrix. ABS resins have a wide variety of applications cated changes in hearing latency and hearing threshold
including automotive parts, pipes and fittings, and similar to previous reports on developmental exposure
domestic and office appliances. Polystyrene is used in to polychlorinated biphenyls (PCBs) (Lilienthal et al.
packaging, electrical and electronic equipment enclo- 2008). It is plausible that the changes in thyroid
sures for televisions, furniture and construction hormone status mediated these effects as thyroid
materials. Another derivative, bis (2-hydroxyethyl hormones play a crucial role in the development of
ether) TBBPA is used as a flame retardant for paperauditory function, and the benchmark dose levels for
and textile adhesives and coatings (Alaee et al. 2003). changes in thyroid hormones (2.3-30.8 mgkg"1 d"1)
and BAEP (1-40 mg kg"1 d"1) were in the same
range (Van der Ven et al. 2008).
(b) Exposure to TBBPA
Products with both additive and chemically bonded
forms of TBBPA have been shown to release TBBPA (ii) Binding to transthyretin
into the environment (Birnbaum & Staskal 2004), TBBPA has an even closer structural relationship to
T4 than PCBs. In vitro competitive binding assays
resulting in detection in sewage sludge (Oberg et al.
2002), soil, sediments, birds, fish (Morris et al. demonstrated that TBBPA binding to human trans-
2004) and air from different occupational settings thyretin (TTR) is more potent than the natural
(Sjödin et al. 2001). TBBPA serves as a source of ligand (Meerts et al. 2000; Hamers et al. 2006). It is
environmental BPA as it has been shown to break theorized that these compounds may decrease serum
down to BPA in marine sediments (European Union T4 concentrations by displacing it from the carrier
Risk Assessment Report 2005). proteins, leading to increased clearance. This displace-
Although studies indicate high first-pass metab-ment could also make more T4 available for
olism of TBBPA in rats and humans owing to rapid deiodination, leading to increased formation of T
conjugation with glucuronic acid and eliminationreverse
in T3.
the bile (Kuester et al. 2007), TBBPA has been

detected in cow and human milk (Thomsen et al. (iii) Binding to thyroid hormone receptor and
2002a; Antignac et al 2008), human serum (e.g. thyroid hormone activity
Hayama et al. 2004), human adipose tissue During development, most tadpole tissues are influ-
(Johnson-Restrepo et al. 2008) and umbilical cord
enced by thyroid hormones, making them suitable to
serum (Antignac et al. 2008). Evaluation of BFRs evaluate
in potential disruption of thyroid homeostasis.
archived human serum samples in Norway showed Ana in vivo study simultaneously exposing Rana
temporal increase in concentrations of six PBDE rugosa tadpoles to T3 and TBBPA found TBBPA

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suppression of T3 induced tail shortenings indicating a (e) Exposure to PBDE

thyroid hormone antagonist effect (Kitamura et al. The presence of PBDEs in breast milk, adipose tissue
2005a). While only mild effects on larval development and serum has been confirmed in several studies (as
were observed, a study in Xenopus laevis tadpoles also reviewed in Frederiksen et al. 2009). An examination
suggested thyroid hormone antagonism by TBBPA of a cohort of 4-year-old children revealed that
(Jagnytsch et al. 2006). In vitro, TBBPA competes breast-fed children have 6.5 times higher average
with T3 binding to a nuclear suspension from rat pitu- body burden of total PBDEs than formula-fed chil-
itary Mt/T/e-2 cells (Kitamura et al. 2002) and was dren (Carrizo et al. 2007). Detection of PBDEs in
shown to inhibit the activity of T3 in Chinese hamster liver tissue of human foetuses (Schecter et al. 2007)
ovary cells transfected with human TRa or TRß and in cord blood (e.g. Antignac et al. 2008) demon-
(Kitamura et al. 2005a). strates that in utero exposure is taking place. On a
pro-kilogram basis, studies have described higher
levels of exposure to PBDEs for children than adults
(iv) Sex steroid effects (as reviewed in Frederiksen et al. 2009).
An increase in pituitary weight in male offspring was
noted in the reproductive study (Van der Ven et al. (f) Animal studies investigating developmental
2008), which correlates with previously published exposure to PBDEs
in vitro findings from Kitamura et al. (2002., 2005o), There are more published studies regarding effects fol-
showing that TBBPA increased proliferation of GH3 lowing in vivo exposure to PBDEs than for TBBPA.
cells (rat pituitary cell line) and growth hormone pro- Animal studies have revealed the potential for endo-
duction. Ghisari & Bonefeld-Jorgensen (2005) also crine disruption and effects on neurobehaviour and
observed that TBBPA stimulates GH3 cell growth, the reproductive system.
which was inhibited by the anti-oestrogen ICI
182 780, suggesting that this effect is ER-mediated.
In vitro studies indicate that the lower brominated (i) Thyroid hormone
forms of TBBPA have higher affinity with the ER In rodent studies, perinatal or peripubertal exposure
to PBDEs causes a reduction in T4 while effects on
than the higher brominated analogues (Samuelsen
T3 and TSH are less consistent. Perinatal exposure
et al. 2001). In MCF-7 human breast cancer cells,
TBBPA functioned as a partial ER agonist (Olsen to 1, 10 or 30mgkg~1 d"1 DE-71 (commercial penta-
et al. 2003) and demonstrated mixed agonist/antagon-
mixture) (Zhou et al. 2002) or 18 mg kg" M"1
ist activities in estrogen responsive element (ERE)- (Ellis-Hutchings et al. 2006) did not alter T3 concen-
trations. However, a concomitant decrease in T3 and
luciferase reporter gene assays. The oestrogenic
an increase in thyroid stimulating hormone (TSH) in
activity was confirmed in vivo using the uterotrophic
males only were observed following peripubertal
assay (Kitamura et al. 2005Ò).
Inhibition of oestradiol sulphation by TBBPA has exposure to 30 or 60 mg kg"1 d"1 DE-71 (Stoker et al
2004), and another study reported a decrease in T3 in
been reported in vitro (Kester et al. 2002; Hamers
female rats following exposure to 100 or 300mgkg~
et al. 2006), which suggests the potential for impaired
elimination in vivo leading to increased biologically
1 d1 DE-71 or 60 or lOOmgkg"1 d"1 DE-79 (octa-
active oestradiol concentrations. Environmentally rele-
commercial mixture) on post-natal day (PND) 28-32
vant TBBPA concentrations have been shown to (Zhou et al. 2001). Administration of 300 |xg kg"1 d"1
BDE-99 (2,2/,4,4/,5-pentabromodiphenyl ether) on
decrease reproductive success in zebra fish (Kuiper
gestation day (gd) 6 resulted in a transient decrease in
et al. 2007) and inhibition of oestradiol metabolism
T3 in male offspring on PND 1 with reductions in T4
in lake trout (Jurgella et al. 2006). In male Japanese
occurring in both male and female offspring on PND
quail, however, no oestrogenic effects after embryonic
22 (Kuriyama et al. 2007).
exposure to TBBPA were observed for reproductive
behaviour, plasma testosterone and testicular mor-
phology (Berg et al. 2001; Halldin et al. 2005). (ii) Effects on sex steroids and the reproductive system
Following gestational exposure,, in vivo oestrogen
activity for BDE-99 has been indicated by increased
(d) Products with PBDEs expression of mRNA of oestrogen responsive genes
Two (penta and octa formulations) of the three mainin the uterus (Ceccatelli et al. 2006). Alterations in
commercial mixtures of PBDEs added to polymers the sex hormone profile have been reported, including
for the manufacture of goods are no longer in pro-reductions in circulating oestradiol and testosterone in
duction. The penta mixture was applied to poly- adult male offspring (Lilienthal et al. 2006) and lower
urethane foams used in furniture, mattresses, carpet circulating oestradiol concentrations without changes
pads and automobile seats and styrene plastics used in whole ovarian aromatase activity in young female
for electrical appliances and flame-retardant textiles. rat offspring exposed to 700 ixgkg"1 of BDE-47 on
The octa-technical mixture was blended with ABS gd 6 (Talsness et al. 2008). Possible impairment of
resins used in automobile electronics, home and androgen function following high-dose peripubertal
office appliances and high-impact sport equipmentexposure to DE-7 1 was indicated by postponed pub-
erty and delayed growth of androgen-dependent tis-
and toys. The deca product is added to a variety of
polymers, and examples of end products include in male rats without an effect on circulating
sues
fabric backings and housings for electronics testosterone concentrations (Stoker et al. 2004).
(Frederiksen et al. 2008). Additional in vitro studies by the same group suggest

31.125.186.252 on Tue, 14 Nov 2023 19:46:37 +00:00
that the observed effects may be because of binding of epithelium leading to impairment of normal spermato-
some of the congeners in the mixture acting as antag- genesis in adult rat offspring can also be speculated.
onists to the androgen receptor (Stoker et al. 2005). In adult female offspring, ultrastructural changes in
Functional changes to the gonads have been the ovary following low-dose gestational exposure to
observed following in utero exposure to PBDEs. either PBDE-99 (Talsness et al. 2005) or BDE-47
Administration of an agent used to treat hyperthyroid- (Talsness et al. 2008) and effects on folliculogenesis
ism, 6-w-propyl-2-thiouracil (5mgl"1 drinking water after administration of 1 or lOmgkg"1 d"1 of BDE-
on gd 7-21), or 60 or 300 fig BDE-99 kg"1 on gd 699 during gestation (Lilienthal et al. 2006) were
(Kuriyama et al. 2007) resulted in a reduction in observed. Altered folliculogenesis evaluated around
spermatid and sperm counts without an influence onthe time of puberty after low-dose exposure to BDE-
circulating testosterone concentrations in adult Fl 47 during gestation has also been reported (Talsness
males (Kuriyama et al. 2005). Whether the impaired et al. 2008). The changes in the latter study were
spermatogenesis is accompanied by changes in the characterized by a reduction in antral follicle numbers
testicular cell population based on DNA ploidy (flow and circulating estradiol concentrations. Whether
cytometry analysis) was examined in isolated testicular these changes are because of thyroid hormone dis-
cells from the other testis (12 per group) of the same ruption or alterations in gonadotropins and/or sex
animals. DNA staining was performed by suspending hormones is unclear.
the cells in phosphate buffered saline with The animal data thus far suggest that PBDEs may
affect the reproductive system via alterations in thyroid
100 juLg ml"1 ribonuclease A and 50 juug ml"1 propidium
iodide. Propidium iodide fluorescence was measured at
hormone profile and/or sex steroid action. Aberrations
620 nm to differentiate between mature haploidin cells
thyroid hormone status are known to adversely
(elongated spermatid), immature haploid cells (round/ affect reproduction. In animal studies, thyroid hor-
elongating spermatid) and diploid cells (spermatogonia, mone has been shown to play an integral role in testi-
spermatocyte, Sertoli cells, Ley dig cells). The number cularofdevelopment (Cooke et al. 1992) and affect
Sertoli cells in the seminiferous epithelium is related ovarian
to follicular maturation (Baldridge et al. 2004).
sperm production since each cell supports a finite
number of germ cells (Rüssel et al. 1990). This cell
number was also determined in histological sections (iii) Neurobehaviour
from other Fl males (six per group) on PND 110. The period of rapid brain growth represents a particu-
Sertoli cell nucleoli were counted in 25 round or nearly larly vulnerable developmental window to insults and
round seminiferous tubule cross-sections chosen at is characterized by a dramatic increase in the number
random, and 25 Sertoli cell nucleoli diameters were of cells and myelination, cell migration, dendritic and
measured for each animal. These counts were corrected axonal growth and the formation of neural connec-
for section thickness and the smallest recognizabletions. Exposure to PBDEs during the brain growth
nucleolar profile (cap section) as described previously spurt of mice modified spontaneous motor behaviour
(Rüssel et al 1990). and habituation to new surroundings (e.g. Viberg
A statistically significant decrease in the ratio of et al. 2006) and altered levels of proteins involved in
haploid/diploid cells was observed in the PBDE-99 brain maturation (Viberg et al. 2008). Other studies
group (figure 2), which corroborates the reduced have found changes in spontaneous motor activity fol-
number of spermatid/sperm counts observed. We lowing early post-natal exposure to mice, as well as
observed slight differences in the ratio of mature effects on one measure of the ontogeny of sensori-
haploid (mostly elongated spermatid)/diploid cells in motor integration (Rice et al. 2007) and subtle differ-
treated animals, and this effect was more pronounced ences in neuromotor development (Branchi et al.
when the ratio of immature haploid (round/elongating 2002; Gee & Moser 2008). In addition, examination
spermatid)/diploid cells was compared with controls. of cognitive function revealed deficits as mice exhib-
No change in the number of Sertoli cells/seminiferous ited impaired learning and memory on the Morris
tubule cross-section was observed among the groups water maze test following early post-natal PBDE
(figure 2), indicating that the reduction in haploid exposure (Viberg et al. 2003).
cells is because of another cause and supporting the Administration of BDE-99 to rats during gestation
finding that the changes in these ratios are owing to at a dose (300 ug kg"1 on gd 6) resulting in dam adi-
reductions in the haploid populations. The observed pose tissue concentrations (Kuriyama et al. 2007)
impaired spermatogenesis in male offspring exposed only slightly higher than those reported for this
to low-dose BDE-99 during development (Kuriyama congener in humans (Johnson-Restrepo et al. 2005)
et al. 2005) has been confirmed by flow cytometry led to hyperactivity in the rat offspring (Kuriyama
analysis and is not mediated by reduced numbers of et al. 2005).
Sertoli cells. Alternatively, a hormonal-dependent
mechanism can be proposed as sperm production is
dependent on permissive actions of follicle stimulating (g) Relevance of exposure to flame retardants
hormone (FSH) and testosterone and, therefore, lutei- for human health
nizing hormone (LH). Although significant differences (i) Reproduction
in testosterone and LH concentrations in serum from It is known that diseases of the thyroid gland affect the
adult animals were not found, the possibility of hor- reproductive capacity of women. In particular,
monal changes during early development cannot be hypothyroid women may exhibit anovulation, and
ruled out. Functional changes in the seminiferoushypothyroidism is associated with hyperprolactinaemia,

31.125.186.252 on Tue, 14 Nov 2023 19:46:37 +00:00
Figure 2. Number of Sertoli cells per tubule cross-section in adult male offspring (Fl) on PND 110 and flow cytometry analy-
sis of testicular cell population on the basis of their DNA ploidy in adult rats on PND 140. Gravid female rats were adminis-
tered per gavage either vehicle (control) or 60 or 300 |xg BDE-99 (kg bw)~ 1 (PBDE-60 or PBDE-300) on gd 6. A fourth group
received 5 mg 6-w-propyl-2-thiouracil (PTU)T1 in drinking water from gd 7-21. ANOVA followed by Dunnett r-test,
*p < 0.05.
in granulosa cells, which produce steroids and provide

which inhibits the release of pituitary gonadotropin and
gonadal steroids. growth factors interacting with the oocyte.
Although less is known about the role of thyroid In addition, alterations in sex steroid concentrations
hormones in the development of the reproductive or function and LH levels have been reported in
system, it is believed that they are important for animal studies for PBDEs, indicating the potential
gonad development in both sexes (Cooke et al. to adversely affect human reproduction. Two epide-
2004). Animal studies and in vitro studies demonstratemiological studies indicate that exposure may be
that TBBPA and PBDEs interfere with thyroid hor- associated with adverse affects on the testis.
mone action, and the function of both the ovary and Preliminary data from a pilot study performe
Japan suggest an inverse relationship between
the testis has been altered following in utero exposure
to PBDEs. Thyroid hormones indirectly affect sperm 153 (2,2/4,4/,5,5/-hexabromodiphenyl ether)
production by regulating the number of Sertoli cells, concentrations and sperm concentration in young
which act as nurse cells for developing sperm. It Japanese males (Akutsu et al. 2008). A larger study
should be noted, however, that the new data presented relating information regarding in utero and early devel-
here indicate that the observed reduction in sperm opmental exposure to PBDEs with cryptorchidism
count following gestational BDE-99 exposure was involved 86 Danish and Finnish newborn boy-
not associated with changes in Sertoli cell number. mother pairs. Associations between PBDE contami-
In the ovary, thyroid hormone receptors are present nation of human breast milk and cryptorchidism and

31.125.186.252 on Tue, 14 Nov 2023 19:46:37 +00:00
increased gonadotropin release to support normal Development and testing of medications involves a
testosterone production were observed (Main et al. series of evaluations culminating in human clinical
2007). Although there was no significant difference trials before marketing is approved. This is quite
in the placental concentrations3 the sum of PBDEs in different from the situation with chemicals, whose
breast milk was higher in cryptorchid boys than in con- presence in biota and humans is inadvertent. In the
trols and was positively correlated with infant serum field of toxicology, information regarding potential
LH concentration. The authors suggest that the lack human health effects is mainly derived from exper-
of correlation between the PBDE concentrations in imental studies and, when available, from epidemiolo-
the placental and breast milk samples may be that
gical studies. Difficulties are not only encountered
the placenta represents the situation at delivery with extrapolation
as from animal models to humans,
one would find in a single blood sample and but notepidemiological
the studies are also thwarted by draw-
long-term exposure. backs such as controlling for confounding factors. In
Although the exposure time frames are not compar- particular, subjects are exposed to an assortment of
able, an increase in LH was also reported forchemicals adult on a daily basis and, often, lack of data
male rats exposed to 60 mgkg"1 d"1 of DE-71 regarding
for 3 the extent of exposure at what may have
days (Stoker et al. 2005). As indicated previously, been the critical time frame. One of the goals of toxi-
InsB and androgen play roles in testicular descent. cology is to identify effects in animal models with the
LH regulates testosterone production and plays a aim to lower the risks of negatively impacting human
role in the differentiation of Leydig cells, which must health. Implicit in this task is that toxicological data,
reach a certain stage before production of InsB derived from animal studies indicating a potential for
occurs (Sadeghian et al. 2005). The rate of this adverse effects, serve as a basis to limit exposure
maturation process in rats has been reported to bebefore effects appear or are confirmed in humans.
influenced by T3 (Mendis-Handagama et al. 2007). The evidence from animal studies on single exposures
Alterations in thyroid hormone profile or changes in to the chemicals discussed here suggests the potential
the status of the hypothalamo- pituitary -testicular for risk to human health. Moreover, data derived
axis could influence testicular descent by impacting from co-exposure studies support the contention that
InsB formation. the assortment of chemicals to which we are exposed
on a daily basis increases the likelihood of health
(ii) Neurodevelopment effects. The high prevalence of body burdens of
Thyroid hormone is crucial for growth and development these chemicals and simultaneous exposure to a
and in particular, for neurodevelopment. Decreases number
in of substances, in conjunction with the fact
foetal and maternal thyroid hormone are known to that the highest concentrations have been demon-
impact neuropsychological development in humans, strated in the developing young, a sensitive subpopu-
and impaired achievement on neuropsychological tests lation of society, indicate the need to decrease the
can occur even when maternal hypothyroidism is exposure to these compounds.
subclinical (Haddow et al. 1999). An evaluationWe
ofwould like to thank Brigitte Woelffel, Zeynep Akkoc and
human thyroid hormone status and PBDE exposure
Lars Niemann for their excellent technical assistance.
Support for the previously unpublished data on BDE-99
was performed in China. TSH and serum concen-
trations of PBDEs were found to be significantly was through a grant from the Umweltbundesamt (Federal
Environment Agency, grant No. 29965221/04).
increased in subjects living close to an electronic waste
site compared with those living 50 km away, suggesting
hormone disruption (Yuan et al. 2008).
Aberrations in thyroid hormone homeostasis caused
REFERENCES
by PBDEs and TBBPA raise concerns regarding their
Akingbemi, B. T, Ge5 R., Klinefelter, G. R.3 Zirkin, B. R
potential to influence child neurodevelopment. Animal Hardy, M. P. 2004 Phthalate-induced Leydig cell hyper
studies indicate changes in behaviour following plasia is associated with multiple endocrine disturbance
exposure to PBDEs during a critical developmental Proc. NatlAcad. Sci. USA 101, 775-780. (doi:10.1073/
window, which may be mediated through changes in pnas.0305977101)
thyroid hormones or direct neurotoxicity. Akutsu, K., Takatori, S., Nozawa, S., Yoshiike, M.,
Data regarding neurotoxicants indicate that there is Nakazawa, H., Hayakawa, K., Makino, T. & Iwamoto, T.
a continuum of toxic outcomes at low doses, i.e. 2008 Polybrominated diphenyl ethers in human serum
chronic daily exposures, which do not induce overt and sperm quality. Bull. Environ. Contam. Toxicol. 80,
clinical symptoms (Grandjean & Landrigan 2006). 345-350. (doi:10.1007/s00 128-008-9370-4)
Alaee, M., Arias, P., Sjödin, A. & Bergman, A. 2003 An
The authors suggest that neurodevelopmental dis-
overview of commercially used brominated flame retard-
orders associated with exposure to known human neu-
ants, their applications, their use patterns in different
rotoxicants and untested chemicals have resulted in a
countries/regions and possible modes of release.
veiled pandemic, incurring significant costs to society Environ. Int. 29, 683-689. (doi:10.1016/S0160-
because of lowered productivity and reductions in 4120(03)00121-1)
intelligence (Grandjean & Landrigan 2006). Alonso-Magdalena, P., Laribi, O., Ropero, A. B., Fuentes, E.,
Ripoll, C, Soria, B. & Nadal, A. 2005 Low doses of
bisphenol A and diethylstilbestrol impair Ca2+ signals in
5. GENERAL CONCLUSIONS pancreatic alpha-cells through a nonclassical membrane
estrogen receptor within intact islets of Langerhans.
Exposure of humans to Pharmaceuticals is deliberate,
with the intention of achieving a desired effect. Environ. Health Perspect. 113, 969-977.

31.125.186.252 on Tue, 14 Nov 2023 19:46:37 +00:00
Alonso-Magdalena, P., Morimoto, S., Ripoll, C, Fuentes, E. polycarbonate baby bottles after dishwashing, boiling and
& Nadal, A. 2006 The estrogenic effect of bisphenol A brushing. FoodAddit. Contam. 20, 684-689. (doi:10.1080/
disrupts pancreatic beta-cell function in vivo and induces 0265203031000119061)
insulin resistance. Environ. Health Perspect. 114, 106-112. Burridge, E. 2003 Bisphenol A: product profile. Eur. Chem.
Alonso-Magdalena, P., Ropero, A. B., Carrera, M. P., News 14-20, 17.
Cederroth, C. R., Baquie, M., Gauthier, B. R., Nef, S.,Calafat, A. M., Ye, X., Wong, L. Y, Reidy, J. A. & Needham,
Stefani, E. & Nadal, A. 2008 Pancreatic insulin content L. L. 2008 Exposure of the U.S. population to bisphenol
regulation by the estrogen receptor ER alpha. PLoS A and 4-tertiary-octylphenol: 2003-2004. Environ.
ONE 3, e2069. (doi:10.1371/journal.pone.0002069) Health Perspect. 116, 39-44.
Andrade, A. J., Grande, S. W., Talsness, C. E., Grote, K., Canada 2008 Draft screening assessment for the challenge
Golombiewski, A., Sterner-Kock, A. & Chahoud, I. phenol, 4,4/-(l-methylethylidene)bis-(bisphenol A).
2006(2 A dose -response study following in utero and Chemical Abstracts Service Registry Number 80-05-7.
lactational exposure to di-(2-ethylhexyl) phthalate See http://www.ec.gc.ca/substances/ese/eng/challenge/
(DEHP): effects on androgenic status, developmental batch2/batch2_80-05-7.cfm.
landmarks and testicular histology in male offspring rats. Carrizo, D., Grimait, J. O., Ribas-Fito, N., Sunyer, J. &
Toxicology 225, 64-74. (doi:10.1016/j.tox.2006.05.007) Torrent, M. 2007 Influence of breastfeeding in the
Andrade, A. J., Grande, S. W., Talsness, C. E., Gericke, C, accumulation of polybrominated diphenyl ethers during
Grote, K., Golombiewski, A., Sterner-Kock, A. & the first years of child growth. Environ. Sci. Technol 41,
Chahoud, I. 200 6b A dose response study following in 4907-4912. (doi:10.1021/es070217u).
utero and lactational exposure to di-(2-ethylhexyl) phtha- Ceccatelli, R., Faass, O., Schlumpf, M. & Lichtensteiger, W.
late (DEHP): reproductive effects on adult male offspring2006 Gene expression and estrogen sensitivity in rat uterus
rats. Toxicology 228, 85-97. (doi:10.1016/j.tox.2006.08. after developmental exposure to the polybrominated
020) diphenylether PBDE-99 and PCB. Toxicology 220, 104-
Andrade, A. J., Grande, S. W., Talsness, C. E., Grote, K. & 116. (doi:10.1016/j.tox.2005. 12.004).
Chahoud, I. 2006c A dose-response study following in Cooke, P. S., Porcelli, J. & Hess, R. A. 1992 Induction of
utero and lactational exposure to di- (2-ethylhexyl) -phtha- increased testis growth and sperm production in adult
late (DEHP): non-mono tonic dose -response and low rats by neonatal administration of the goitrogen
dose effects on rat brain aromatase activity. Toxicology propylthiouracil (PTU): the critical period. Biol Reprod.
227, 185-192. (doi:10.1016/j.tox.2006.07.022) 46, 146-154. (doi: 10. 1095/biolreprod46. 1.146)
Antignac, J. P. et al 2008 Exposure assessment of fetus and Cooke, P. S., Holsberger, D. R., Witorsch, R. J., Sylvester, P. W.,
newborn to brominated flame retardants in France: pre- Meredith, J. M., Treinen, K. A. & Chapín, R. E. 2004
liminary data. Mol Nutr. Food Res. 52, 258-265. (doi:10. Thyroid hormone, glucocorticoids, and prolactin at the
1002/mnfr.200700077) nexus of physiology, reproduction, and toxicology.
Bae, B., Jeong, J. H. & Lee, S. J. 2002 The quantifica- Toxicol Appi Pharmacol 194, 309-335. (doi:10.1016/j.
tion and characterization of endocrine disruptor bis- taap.2003.09.016).
phenol-A leaching from epoxy resin. Water Sci. Technol Crain, D. A., Eriksen, M., Iguchi, T, Jobling, S., Laufer, H.,
46, 381-387. LeBlanc, G. A. & Guillette Jr, L. J. 2007 An ecological
Baldridge, M. G., Stahl, R. L., Gerstenberger, S. L., Tripoli, assessment of bisphenol-A: evidence from comparative
V. & Hutz, R. J. 2004 In utero and lactational exposure ofbiology. Reprod. Toxicol 24, 225-239. (doi:10.1016/j.
Long-Evans rats to ammonium perchlorate (AP) disrupts reprotox.2007.05.008)
ovarian follicle maturation. Reprod. Toxicol 19, 155-161. Dessi-Fulgheri, F., Porrini, S. & Farabollini, F 2002 Effects
(doi:10.1016/j.reprotox.2004.07.002). of perinatal exposure to bisphenol A on play behavior of
Barlow, N. J. & Foster, P. M. 2003 Pathogenesis of male female and male juvenile rats. Environ. Health Perspect.
reproductive tract lesions from gestation through adult- 110(Suppl. 3), 403-407.
hood following in utero exposure to di(w-butyl) phthalate. Dodds, E. C. & Lawson, W. 1936 Synthetic oestrogenic
Toxicol Pathol 31, 397-410. agents without the phenanthrene nucleus. Nature 137,
Barr, D. B., Wang, R. Y & Needham, L. L. 2005 Biologic 996. (doi:10.1038/137996a0).
monitoring of exposure to environmental chemicals Dodds, E. C, Lawson, W. & Noble, R. L. 1938 Biological
throughout the life stages: requirements and issues for effects of the synthetic oestrogenic substance 4: 4'-dihy-
consideration for the National Children's Study. droxy- a: B-dimethylstilbene. Lancet 234, 1389-1391
Environ. Health Perspect. 113, 1083-1091. Dostal, L. A., Chapin, R. E., Stefanski, S. A., Harris,
Beltowski, J., Jamroz-Wisniewska, A. & Widomska, S. 2008 M. W. & Schweiz, B. A. 1988 Testicular toxicity and
Adiponectin and its role in cardiovascular diseases. reduced Sertoli cell numbers in neonatal rats by di (2-
Cardiovasc. Hematol Disord. Drug Targets 8, 7-46. ethylhexyl) phthalate and the recovery of fertility
(doi:10. 2174/187152908783884920) as adults. Toxicol. Appi Pharmacol 95, 104-121.
Berg, C, Halldin, K. & Brunström, B. 2001 Effects of (doi: 10.101 6/S004 1 -008X(88)800 1 2-7)
bisphenol A and tetrabromobisphenol A on sex organEFSA 2006 Opinion of the Scientific Panel on Food
development in quail and chicken embryos. Environ. Additives, Flavourings, Processing Aids and Materials in
Toxicol. Chem. 20, 2836-2840. (doi:10. 1897/1551- Contact with Food on a request from the Commission
5028(2001)020<2836:EOBAAT>2.0.CO;2). related to 2,2-BIS(4-HYDROXYPHENYL) PROPANE
Birnbaum, L. S. & Staskal, D. F. 2004 Brominated flame (Bisphenol A). EFSA J. 428, 1-76.
retardants: cause for concern? Environ. Health Perspect. Ellis-Hutchings, R. G., Cherr, G. N., Hanna, L. A. & Keen,
112, 9-17. (doi:10.1289/chp.6559) C. L. 2006 Polybrominated diphenyl ether induced
Branchi, L, Alleva, E. & Costa, L. G. 2002 Effects of alterations in vitamin A and thyroid hormone concen-
perinatal exposure to a polybrominated diphenyl ether trations in the rat during lactation and early postnatal
(PBDE 99) on mouse neurobehavioural development. development. Toxicol. Appi Pharmacol 215, 135-145.
Neurotoxicology 23, 375-384. (doi:10.1016/S0161- (doi:10.1016/j.taap.2006.02.008)
813X(02)00078-5). Environmental Working Group 2007 Bisphenol A: toxic
Brede, C, Fjeldal, P., Skjevrak, I. & Herikstad, H. 2003 plastics chemical in canned food. See www.erg.org/
Increased migration levels of bisphenol A from node/20933.

31.125.186.252 on Tue, 14 Nov 2023 19:46:37 +00:00
European Union Risk Assessment Report 2005 European ovarian function during pregnancy in female Long
Union Risk Assessment Report on 2,2/,6,6/-tetrabromo- Evans hooded rats. Toxicol Sci. 93, 189-195. (doi:10.
4,4/-isopropylene dipenol (tetrabromobisphenol-A) . 1093/toxsci/kfl035)
CAS no. 79-94-7, EINECS no. 201-236-9, European Guillette Jr, L. J. Crain, D. A., Rooney, A. A. & Pickford, D. B.
Chemicals Bureau, Ispra, Italy. 1995 Organization versus activation: the role of endocrine-
Farabollini, R, Porrini, S., Della Seta, D., Bianchi, E & disrupting contaminants (EDCs) during embryonic develop-
Dessi-Fulgheri, F. 2002 Effects of perinatal exposure toment in wildlife. Environ. Health Perspect. 103, 157-164.
bisphenol A on sociosexual behavior of female and male(doi: 10.2307/3432527)
rats. Environ. Health Perspect. 110(Suppl. 3), 409-414.Gupta, C. 2000 Reproductive malformation of the male
Fisher, J. S., Macpherson, S., Marchetti, N. & Sharpe, R. M. offspring following maternal exposure to estrogenic
2003 Human 'testicular dysgenesis syndrome': a possiblechemicals. Proc. Soc. Exp. Biol Med. 224, 61-68. (doi:
model using in-utero exposure of the rat to dibutyl phtha-10.1046/J.1525-1373.2000.22402.X)
late. Hum. Reprod. 18, 1383-1394. (doi:10.1093/ Guvenius, D. M., Aronsson, A., Ekman-Ordeberg, G.,
humrep/deg273) Bergman, A. & Norén, K. 2003 Human prenatal and
Foster, P. M. 2006 Disruption of reproductive development postnatal exposure to polybrominated diphenyl ethers,
in male rat offspring following in utero exposure to phtha- polychlorinated biphenyls, polychlorobiphenylols, and
late esters. Int. J. Androl. 29, 140-147. (doi:10.1 1 1 1/j. pentachlorphenol. Environ. Health Perspect. Ill, 1235-
1365-2605.2005. 00563.x) 1241. (doi:10.1289/ehp.5946)
Foster, P. M., Cook, M. W., Thomas, L. V, Walters, D. G. & Haddow, J. E. et al 1999 Maternal thyroid deficiency during
Gangolli, S. D. 1983 Differences in urinary metabolic pregnancy and subsequent neuropsychological develop-
profile from di-w-butyl phthalate-treated rats and ham- ment of the child. N. Engl. J. Med. 341, 549-555.
sters. A possible explanation for species differences in sus- (doi:10.1056/NEJM199908193410801)
ceptibility to testicular atrophy. Drug Metab. Dispos. 11, Halldin, K., Axelsson, J. & Brunström, B. 2005 Effects of
59-61. endocrine modulators on sexual differentiation and repro-
Frederiksen, M., Vorkamp, K., Thomsen, M. & Knudsen, ductive function in male Japanese quail. Brain Res. Bull.
L. E. 2009 Human internal and external exposure to 65, 211-218. (doi:10.1016/j.brainresbull.2004.1 1.020)
PBDEs - a review of levels and sources. Int. J. Hyg. Hallmark, N. et al 2007 Effects of monobutyl- and di-(w-
Environ. Health 212, 109-135. (doi:10.1016/j.ijheh. butyl) phthalate in vitro on steroidogenesis and Leydig
2008.04.005) cell aggregation in fetal testis expiants from the rat: com-
Fujimoto, T., Kubo, K. & Aou, S. 2006 Prenatal exposure to parison with effects in vivo in the fetal rat and neonatal
bisphenol A impairs sexual differentiation of exploratory marmoset and in vitro in the human. Environ. Health
behavior and increases depression-like behavior in rats. Perspect. 115, 390-396. (doi:10.1289/ehp.9490)
Brain Res. 1068, 49-55. (doi:10.1016/j.brainres.2005. Hamers, T, Kamstra, J. H., Sonneveld, E., Murk, A. J.,
11.028) Kester, M. H. A., Andersson, P. L., Legier, J. &
Gee, J. R. & Moser, V. C. 2008 Acute postnatal exposure to Brouwer, A. 2006 In vitro profiling of the endocrine dis-
brominated diphenylether 47 delays neuromotor onto- rupting potency of brominated flame retardants. Toxicol
geny and alters motor activity in mice. Neurotoxicol. Sci. 92, 157-173. (doi:10.1093/toxsci/kfjl87)
Teratol. 30,79-87. (doi:10.1016/j.ntt.2007. 11.001) Hayama, T., Yoshida, H., Onimaru, S., Yonekura, S.,
Ghisari, M. & Bonefeld-Jorgensen, E. C. 2005 Impact of Kuroki, H., Todoroki, K., Nohta, H. & Yamaguchi, M.
environmental chemicals on the thyroid hormone func- 2004 Determination of tetrabromobisphenol A in
tion in pituitary rat GH3 cells. Mol Cell Endocrinol human serum by liquid chromatography-electrospray ion-
244, 31-41. (doi:10.1016/j.mce.2005.01.013) ization tandem mass spectrometry. J. Chromatogr. B
Grande, S. W., Andrade, A. J., Talsness, C. E., Grote, K. & Analyt. Technol Biomed. Life Sci. 809, 131-136. (doi:
Chahoud, I. 2006 A dose-response study following in 10.1016/j.jchromb.2004.06.013)
utero and lactational exposure to di(2-ethylhexyl)phtha-Heudorf, U, Mersch-Sundermann, V. & Angerer, J. 2007
late: effects on female rat reproductive development. Phthalates: toxicology and exposure. Int. J. Hyg. Environ.
Toxicol Sci. 91, 247-254. (doi:10.1093/toxsci/kfjl28) HealthHO, 623-634. (doi:10.1016/j.ijheh.2007.07.011)
Grande, S. W., Andrade, A. J., Talsness, C. E., Grote, K., Ho, S. M., Tang, W. Y, Belmonte de Frausto, J. & Prins,
Golombiewski, A., Sterner-Kock, A. & Chahoud, I. G. S. 2006 Developmental exposure to estradiol and
2007 A dose -response study following in utero and lacta- bisphenol A increases susceptibility to prostate carcino-
tional exposure to di-(2-ethylhexyl) phthalate (DEHP): genesis and epigenetically regulates phosphodiesterase
reproductive effects on adult female offspring rats. type 4 variant 4. Cancer Res. 66, 5624-5632. (doi: 10.
Toxicology 229, 114-122. (doi: 10. 101 6/j.tox.2006. 10.005) 1 1 58/0008-5472.CAN-06-05 1 6)
Grandjean, P. & Landrigan, P. J. 2006 Developmental neuro- Howdeshell, K. L., Hotchkiss, A. K., Thayer, K. A.,
toxicity of industrial chemicals. Lancet 368, 2167-2178. Vandenbergh, J. G. & vom Saal, F. S. 1999 Exposure to
(doi:10.1016/S0140-6736(06)69665-7) bisphenol A advances puberty. Nature 401, 763-764.
Gray, T. J. & Gangolli, S. D. 1986 Aspects of the testicular Howdeshell, K. L., Furr, J., Lambright, C. R., Rider, C. V,
toxicity of phthalate esters. Environ. Health Perspect. 65, Wilson, V. S. & Gray Jr, L. E. 2007 Cumulative effects of
229-235. (doi: 10.2307/3430 187) dibutyl phthalate and diethylhexyl phthalate on male rat
Gray, T J., Rowland, I. R., Foster, P. M. & Gangolli, S. D. reproductive tract development: altered fetal steroid hor-
1982 Species differences in the testicular toxicity of phtha- mones and genes. Toxicol. Sci. 99, 190-202. (doi: 10.
late esters. Toxicol. Lett. 11, 141-147. (doi: 10. 101 6/0378- 1093/toxsci/kfm069)
4274(82)90119-9) Howdeshell, K. L., Wilson, V. S., Furr, J., Lambright, C. R.,
Gray, L. E., Ostby, J., Furr, J., Price, M., Veeramachanemi, Rider, C. V, Blystone, C. R., Hotchkiss, A. K. & Gray Jr,
D. N. & Parks, L. 2000 Perinatal exposure to the L. E. 2008 A mixture of five phthalate esters inhibits fetal
phthalates DEHP, BBP, and DINP, but not DEP, testicular testosterone production in the Sprague Dawley
DMP, or DOTP, alters sexual differentiation of the male rat in a cumulative dose additive manner. Toxicol. Sci. 105,
rat. Toxicol. Sci. 58, 350-365. (doi:10.1093/toxsci/58.2.350)
153-165. (doi:10.1093/toxsci/kfn077)
Hugo, E. R., Brandebourg, T. D., Woo, J. G., Loftus, J.,
Gray Jr, L. E. Laskey, J. & Ostby, J. 2006 Chronic di-rc-butyl
phthalate exposure in rats reduces fertility and altersAlexander, J. W. & Ben-Jonathan, N. 2008 Bisphenol A

31.125.186.252 on Tue, 14 Nov 2023 19:46:37 +00:00
at environmentally relevant doses inhibits adiponectin Koch, H. M., Preuss, R. & Angerer, J. 2006 Di (2-ethylhexyl)
release from human adipose tissue expiants and phthalate (DEHP): human metabolism and internal
adipocytes. Environ. Health Perspect. 116, 1642-1647. exposure - an update and latest results. Int. J. Androl
(doi:10.1289/ehp. 11537) 29, 155-165. (doi:10.1111/j. 1365-2605. 2005.00607.x)
Ikezuki, Y, Tsutsumi, O., Takai, Y, Kamei, Y. & Taketani, Y Kuester, R. K., Sólyom, A. M., Rodriguez, V. P. & Sipes,
2002 Determination of bisphenol A concentrations in I. G. 2007 The effects of dose, route, and repeated
human biological fluids reveals significant early prenatal dosing on the disposition and kinetics of tetrabromobis-
exposure. Hum. Reprod. 11, 2839-2841. phenol A in male F-344 rats. Toxicol. Sci. 96, 237-245.
IRIS 1988 'Bisphenol A. (CASRN 80-05-7)'. 2002 US-EPA (doi: 10. 1093/toxsci/kfm006)
Integrated Risk Information System Substance file. See Kuiper, R. V, van den Brandhof, E. J., Leonards, P. E. G.,
http://www.epa.gov/iris/subst/0356.htm. van der Ven, L. T. M., Wester, P. W. & Vos, J. G. 2007
Ito, Y, Yokota, H., Wang, R., Yamanoshita, O., Ichihara, G., Toxicity of tetrabromobisphenol A (TBBPA) in zebrafish
Wang, H., Kurata, Y, Takagi, K. & Nakajima, T. 2005 {Danio rerio) in a partial life cycle test. Arch. Toxicol 81,
Species differences in the metabolism of di(2-ethylhexyl) 1-9. (doi:10.1007/s00204-006-0117-x)
phthalate (DEHP) in several organs of mice, rats, and Kurata, Y, Kidachi, F., Yokoyama, M., Toyota, N.,
marmosets. Arch. Toxicol. 79, 147-154. (doi:10.1007/ Tsuchitani, M. & Katoh, M. 1998 Subchronic toxicity
S00204-004-0615-7) of di (2-ethylhexyl) phthalate in common marmosets:
Jagnytsch, O., Opitz, R., Lutz, I. & Kloas, W. 2006 Effects of lack of hepatic peroxisome proliferation, testicular atro-
tetrabromopbisphenol A on larval development and thyr- phy, or pancreatic acinar cell hyperplasia. Toxicol. Sci.
oid hormone-regulated biomarkers of the amphibian 42, 49-56.
Xenopus laevis. Environ. Res. 101, 340-348. (doi: Kuriyama, S. N., Talsness, C. E., Grote, K. & Chahoud, I.
10.1016/j.envres.2005.09.006) 2005 Developmental exposure to low dose PBDE 99:
Johnson-Restrepo, B., Kurunthachalam, K., Rapaport, D. P. & effects on male fertility and neurobehavior in rat off-
Rodan, B. D. 2005 Polybrominated diphenyl ethers and spring. Environ. Health Perspect. 113, 149-154. (doi: 10.
polychlorinated biphenyls in human adipose tissue from 1289/ehp.7421)
New York. Environ. Sci. Technol. 39, 5177-5182. Kuriyama, S. N., Wanner, A., Fidalgo-Neto, A. A., Talsness,
(doi:10.1021/es050399x) C. E., Koerner, W. & Chahoud, I. 2007 Developmental
Johnson-Restrepo, B., Adams, D. H. & Kannan, K. 2008 exposure to low-dose PBDE-99: tissue distribution and
Tetrabromobisphenol A (TBBPA) and hexabromocyclo- thyroid hormone levels. Toxicology 242, 80-90. (doi: 10.
dodecanes (HBCDs) in tissues of humans, dolphins, 1016/j.tox.2007.09.011)
and sharks from the United States. Chemosphere 70, Lahousse, S. A., Wallace, D. G., Liu, D., Gaido, K. W &
1935-1944. (doi: 10. 1016/j.chemosphere.2007. 10.002) Johnson, K. J. 2006 Testicular gene expression profiling
Joskow, R., Barr, D. B., Barr, J. R., Calafat, A. M., following prepubertal rat mono- (2-ethylhexyl) phthalate
Needham, L. L. & Rubin, C. 2006 Exposure to bisphenol exposure suggests a common initial genetic response at
A from bis-glycidyl dimethacrylate-based dental sealants. fetal and prepubertal ages. Toxicol Sci. 93, 369-381.
J. Am. Dent. Assoc. 137, 353-362. (doi: 10. 1093/toxsci/kfl049)
Jurgella, G. R, Marwah, A., Malison, J. A., Peterson, R. &Lake, B. G., Brantom, P. G., Gangolli, S. D., Butterworth,
Barry, T. P. 2006 Effects of xenobiotics and steroids on K. R. & Grasso, P. 1 976 Studies on the effects of orally admi-
renal and hepatic estrogen metabolism in lake trout. nistered di- (2-ethylhexyl) phthalate in the ferret. Toxicology
Gen. Comp. Endocrinol 148, 273-281. (doi:10.1016/ 6, 341-356. (doi:10.1016/0300-483X(76)90038-X)
j.ygcen.2006.03.011) Lamb, J. C, Chapin, R. E., Teague, J., Lawton, A. D. &
Keri, R. A., Ho, S. M., Hunt, P. A., Knudsen, K. E., Reel, J. R. 1987 Reproductive effects of four phthalic
Soto, A. M. & Prins, G. S. 2007 An evaluation of evidence acid esters in the mouse. Toxicol Appi Pharmacol 88,
for the carcinogenic activity of bisphenol A. Reprod. Toxicol 255-269. (doi:10.1016/0041-008X(87)90011-l)
24, 240-252. (doi:10.1016/j.reprotox.2007.06.008) Lang, I. A., Galloway, T. S., Scarlett, A., Henley, W E.,
Kester, M. H. A. et al 2002 Potent inhibition of estrogen sul- Depledge, M., Wallace, R. B. & Melzer, D. 2008
fotransferase by hydroxylated metabolites of polyhaloge- Association of urinary bisphenol A concentration with
nated aromatic hydrocarbons reveals alternative medical disorders and laboratory abnormalities in
mechanism for estrogenic activity of endocrine disrupters. adults. JAMA 300, 1303-1310. (doi:10.1001/jama.300.
J. Clin. Endocrinol. Metab. 87, 1142-1150. (doi:10.1210/ 11.1303)
jc.87.3.1142) Law, R. J., Allchin, C. R., de Boer, J., Covaci, A., Herzke, D.,
Kitamura, S., Jinno, N., Ohta, S., Kuroki, H. & Fujimoto, N. Lepom, P., Morris, S., Tronczynski, J. & de Wit, C. A.
2002 Thyroid hormonal activity of the flame retardants 2006 Levels and trends of brominated flame retardants
tetrabromobisphenol A and tetrachlorobisphenol A. in the European environment. Chemosphere 64, 187-208.
Biochem. Biophys. Res. Commun. 293, 554-559. (doi: (doHO.lOló/j.chemosphere^OOS. 12.007)
10.101 6/S0006-29 1X(O2)OO262-O) Lehmann, K. P., Phillips, S., Sar, M., Foster, P. M. & Gaido,
Kitamura, S. et al 2005a Anti-thyroid hormonal activity of K. W. 2004 Dose-dependent alterations in gene
tetrabromobisphenol A, a flame retardant, and related expression and testosterone synthesis in the fetal testes
compounds: affinity to the mammalian thyroid hormone of male rats exposed to di (rc-butyl) phthalate. Toxicol
receptor, and effect on tadpole metamorphosis. Life Sci. Sci. 81, 60-68. (doi:10.1093/toxsci/kfhl69)
76, 1589-1601. (doi:10.1016/j.lfs.2004.08.030) Leranth, C, Szigeti-Buck, K., Maclusky, N. J. & Hajszan, T
Kitamura, S. et al. 2005Ò Comparative study of the endo- 2007 Bisphenol A prevents the synaptogenic response to
crine-disrupting activity of bisphenol A and 19 related testosterone in the brain of adult male rats. Endocrinology
compounds. Toxicol Sci. 84, 249-259. (doi:10.1093/ 149, 988-994. (doi:10.1210/en.2007-1053)
toxsci/kfi074) Leranth, C, Hajszan, T, Szigeti-Buck, K., Bober, J. &
Koch, H. M., Drexler, H. & Angerer, J. 2004 Internal MacLusky, N. J. 2008 Bisphenol A prevents the synapto-
exposure of nursery-school children and their parents genic response to estradiol in hippocampus and prefrontal
and teachers to di (2-ethylhexyl) phthalate (DEHP). cortex of ovariectomized nonhuman primates. Proc. Nati
Int. J. Hyg. Environ. Health 207, 15-22. (doi: 10. 1078/ Acad. Sci. USA 105, 14 187-14 191. (doi:10.1073/pnas.
1438-4639-00270) 0806139105)

31.125.186.252 on Tue, 14 Nov 2023 19:46:37 +00:00
Li, L. H., Jester Jr5 W. R Laslett, A. L. & Orth, J. M. 2000 A postnatal rat Leydig cell lineage: timing and effects of
single dose of di-(2-ethylhexyl) phthalate in neonatal rats triiodothyronine-treatment. Reproduction 133, 479-485.
alters gonocytes, reduces Sertoli cell proliferation, and (doi: 10.1 530/REP-06-0238)
decreases cyclin D2 expression. Toxicol Appi Pharmacol. Mocarelli, P. et al. 2008 Dioxin exposure, from infancy
166, 222-229. (doi:10.1006/taap.2000.8972) through puberty, produces endocrine disruption and
Lilienthal, H., Hack, A., Roth-Härer, A., Wiehert Grande, S. affects human semen quality. Environ. Health Perspect.
& Talsness, C. E. 2006 Effects of developmental exposure 116, 70-77. (doi: 10.1289/ehp. 10399)
to 2,2/,4,4/,5-pentabromodipheyl ether (PBDE-99) on Morris, S. et al 2004 The distribution and fate of HBCD
sex steroids, sexual development, and sexually dimorphic and TBBP-A brominated flame retardants in North Sea
behavior in rats. Environ. Health. Perspect. 114, 194-201. estuaries and aquatic food webs. Environ. Sci. Technol
(doi:10.1289/ehp.8391) 38, 5497-5504. (doi:10.1021/es049640i)
Lilienthal, H., Verwer, C. M., van der Ven, L. T., Piersma, Myers, J. P. & vom Saal, F. S. 2008 Time to update environ-
A. H. & Vos, J. G. 2008 Exposure to tetrabromobisphenol mental regulations. San Francisco Medi. 81, 30-31.
A (TBBPA) in Wistar rats: neurobehavioral effects in off- Mylchreest, E., Sar, M., Cattley, R. C. & Foster, P. M. 1999
spring from a one-generation reproduction study. Disruption of androgen-regulated male reproductive
Toxicology 246, 45-54. (doi:10.1016/j.tox.2008.01.007) development by di(w-butyl) phthalate during late ges-
Lin, H. et al. 2008 Involvement of testicular growth factors in tation in rats is different from flutamide. Toxicol. Appi
fetal Leydig cell aggregation after exposure to phthalate in Pharmacol. 156, 81-95. (doi: 10. 1006/taap. 1999.8643)
utero. Proc. Nati Acad. Sci. USA 105, 7218-7222. (doi: Nagao, T., Ohta, R., Marumo, H., Shindo, T, Yoshimura, S. &
10.1073/pnas.0709260105) Ono, H. 2000 Effect of butyl benzyl phthalate
Lopez-Cervantes, J. & Paseiro-Losada, P. 2003 in Sprague-Dawley rats after gavage administration: a
Determination of bisphenol A in, and its migration two-generation reproductive study. Reprod. Toxicol 14,
from, PVC stretch film used for food packaging. Food 513-532. (doi:10.1016/S0890-6238(00)00105-2)
Addit. Contam. 20, 596-606. Nagel, S. C, vom Saal, F. S., Thayer, K. A., Dhar, M. G.,
MacLusky, N. J., Hajszan, T. & Leranth, C. 2005 The Boechler, M. & Welshons, W. V. 1997 Relative binding
environmental estrogen bisphenol A inhibits estrogen- affinity-serum modified access (RBA-SMA) assay pre-
induced hippocampal synaptogenesis. Environ. Health dicts the relative in vivo bioactivity of the xenoestrogens
Perspect. 113, 675-679. bisphenol A and octylphenol. Environ. Health Perspect.
Main, K. M. et al. 2006 Human breast milk contamination 105, 70-76. (doi: 10.2307/3433065)
with phthalates and alterations of endogenous reproduc- Nerin, C, Fernandez, C, Domeño, C. & Salafranca, J. 2003
tive hormones in infants three months of age. Environ. Determination of potential migrants in polycarbonate
Health Perspect. 114, 270-276. (doi:10.1289/ehp.8075) containers used for microwave ovens by high-perform-
Main, K. M., Kiviranta, H., Virtanen, H. E., Sundqvist, E., ance liquid chromatography with ultraviolet and fluor-
Tuomisto, J. T, Tuomisto, J., Vartiainen, T., Skakkebaek, escence detection. J. Agrie. Food Chem. 51, 5647-5653.
N. E. & Toppari, J. 2007 Flame retardants in placenta and (doi:10.1021/jf034330p)
breast milk and cryptorchidism in newborn boys. Environ. Newbold, R. R., Jefferson, W. N., Padilla-Banks, E. &
Health Perspect. 115, 1519-1526. (doi: 10.1289/ehp. 9924) Haseman, J. 2004 Developmental exposure to diethylstil-
Markey, C. M., Coombs, M. A., Sonnenschein, C. & Soto, bestrol (DES) alters uterine response to estrogens in
A. M. 2003 Mammalian development in a changing prepubescent mice: low versus high dose effects. Reprod.
environment: exposure to endocrine disruptors reveals Toxicol. 18, 399-406. (doi:10.1016/j.reprotox.2004.01.
the developmental plasticity of steroid-hormone target 007)
organs. Evol. Dev. 5, 67-75. (doi:10.1046/j.l525-142X. Newbold, R. R., Jefferson, W. N. & Padilla-Banks, E. 2007
2003.03011.x) Long-term adverse effects of neonatal exposure to bisphenol
Martino-Andrade, A. J., Morais, R. N., Botelho, G. G., A on the murine female reproductive tract. Reprod. Toxicol
Muller, G., Grande, S. W., Carpentieri, G. B., Leão, 24, 253-258. (doi:10.1016/j.reprotox.2007.07.006)
G. M. & Dalsenter, P. R. 2008 Coadministration of Norén, K. & Meironyté, D. 2000 Certain organochlorine
active phthalates results in disruption of foetal testicular and organobromine contaminants in Swedish human
function in rats. Int. J. Androl. [Epub ahead of print].milk in perspective of past 20-30 years. Chemosphere 40,
(doi:10.1111/j.l365-2605. 2008. 00939.x) 1111-1123. (doi: 10.1016/S0045-6535(99)00360-4)
Matsumoto, J., Yokota, H. & Yuasa, A. 2002 Developmental Oberg, K., Warman, K. & Oberg, T. 2002 Distribution
increases in rat hepatic microsomal UDP-glucuronosyl- and levels of brominated flame retardants in sewage
transferase activities toward xenoestrogens and decreases sludge. Chemosphere 48, 805-809. (doi:10.1016/S0045-
during pregnancy. Environ. Health Perspect. 110, 193-196. 6535(02)00113-3)
Matsumoto, A., Kunugita, N., Kitagawa, K., Isse, T., Oyama, Oehlmann, J. et al. 2009 A critical analysis of the biological
T, Foureman, G. L., Morita, M. & Kawamoto, T. 2003 impacts of plasticizers on wildlife. Phil. Trans. R. Soc. B
Bisphenol A levels in human urine. Environ. Health 364, 2047-2062. (doi:10.1098/rstb.2008.0242)
Perspect. Ill, 101-104. Ogura, Y, Ishii, K., Kanda, H., Kanai, M., Arima, K.,
Mckee, R. H., Butala, J. H., David, R. M. & Gans, G. 2004 Wang, Y & Sugimura, Y 2007 Bisphenol A induces per-
NTP Center for the evaluation of risks to human repro- manent squamous change in mouse prostatic epithelium.
duction reports on phthalates: addressing the data gaps. Differentiation IS, 745-756. (doi: 10.1 1 1 1/j. 1432-0436.
Reprod. Toxicol. 18, 1-22. (doi:10.1016/j.reprotox.2003. 2007.00177.x)
09.002) Olsen, C. M., Meussen-Elholm, E. T. M., Samuelsen, M.,
Meerts, I. A. T. M., van Zanden, J. J., Luijks, E. A. C, van Holme, J. A. & Hongslo, J. K. 2003 Effects of the
Leeuwen-Bol, I., Goran, M., Jakobsson, E., Bergman, À. & environmental oestrogens bisphenol A, tetrachlorobisphe-
Brouwer, A. 2000 Potent competitive interactions of some nol A, tetrabromobisphenol A, 4-hydroxybiphenyl and
brominated flame retardants and related compounds with 4,4/-dihydroxybiphenyl on oestrogen receptor binding,
human transthyretin in vitro. Toxicol. Sci. 56, 95-104. cell proliferation and regulation of oestrogen sensitive
(doi: 10.1093/toxsci/56. 1.95) proteins in the human breast cancer cell line MCF-7.
Mendis-Handagama, S. M., Ariyaratne, H. B., Mrkonjich, L. & Pharmacol. Toxicol. 92, 180-188. (doi: 10.1 034/j. 1600-
Ivell, R. 2007 Expression of insulin-like peptide 3 in the 0773.2003.920408.x)

31.125.186.252 on Tue, 14 Nov 2023 19:46:37 +00:00
Palanza, P., Howdeshell, K. L., Parmigiani, S. & vom Saal, Samuelsen, M., Olsen, C, Holme, J. A., Meussen-Elholm,
F. S. 2002 Exposure to a low dose of bisphenol A E., Bergmann, A. & Hongslo, J. K. 2001 Estrogen-like
during fetal life or in adulthood alters maternal behavior properties of brominated analogs of bisphenol A in the
in mice. Environ. Health Perspect. 110, 415-422. MCF-7 human breast cancer cell line. Cell Biol. Toxicol.
Palanza, P. L., Gioiosa, L., Parmigiani, S. & vom Saal, F. S. 17, 139-151. (doi:10.1023/A:101 1974012602)
2008 Effects of developmental exposure to bisphenolSchecter,
A A., Johnson-Welch, S., Tung, K. C, Harris, T,
on brain and behavior in mice. Environ. Res. 108, Papke, O. & Rosen, R. 2007 Polybrominated diphenyl
150-157. (doi:10.1016/j.envres.2008.07.023) ether (PBDE) levels in livers of U.S. human fetuses and
Parks, L. G., Ostby, J. S., Lambright, C. R., Abbott, B. D., newborns. J. Toxicol. Environ. Health A 70, 1-6.
Klinefelter, G. R., Barlow, N. J. & Gray, L. E. 2000 (doiilO. 1080/15287390600748369)
The plasticizer diethylhexyl phthalate induces malfor- Schoeters, G., Den Hond, E., Dhooge, W, van Larebeke, N. &
mations by decreasing fetal testosterone synthesis during Leijs, M. 2008 Endocrine disruptors and abnormalities of
sexual differentiation in the male rat. Toxicol. Sci 5, pubertal development. Basic Clin. Pharmacol Toxicol 102,
339-349. 168-175. (doi: 1 0.1 111/j.l 742-7 843.2007.00 180.x)
Pugh Jr, G., Isenberg, J. S., Kamendulis, L. M.,Schönfelder, Ackley, D. G.,C,
Wittfoht, W, Hopp, H., Talsness, C. E.,
Clare, L. J., Brown, R., Lington, A. W., Smith, Paul,J.M.H.& &
Chahoud, L 2002 Parent bisphenol A
Klauning, J. E. 2000 Effects of di-isononyl phthalate, accumulation in human maternal-fetal-placental unit.
di-2-ethylhexyl phthalate, and clofibrate in cynomolgus Environ. Health Perspect. 110, A703-A707.
monkeys. Toxicol. Sci 56, 181-188. (doi:10.1093/toxsci/ Sharpe, R. M. & Skakkebaek, N. E. 2008 Testicular dysgen-
56.1.181) esis syndrome: mechanistic insights and potential
Rice, D. C, Reeve, E. A., Herlihy, A., Zoeller, R. T., new downstream effects. Fértil Steril 89, 33-38. (doi:
Thompson, W. D. & Markowski, V. P. 2007 10. 1016/j.fertnstert.2007. 12.026)
Developmental delays and locomotor activity in the Sheehan, D. M. 2005 No-threshold dose -response curves
C47BL6/L mouse following neonatal exposure to the for nongeno toxic chemicals: findings and applications for
fully-brominated PBDE, decabromodiphenyl ether. risk assessment. Environ. Res. 100, 93-99. (doi:10.1016/
Neurotoxicol. Teratol 29, 511-520. (doi:10.1016/n.ntt. j.envres.2005.09.002)
2007.03.061) Sheehan, D. M., Willingham, E., Gaylor, D., Bergeron,
Richter, C. A., Birnbaum, L. S., Farabollini, F., Newbold, J. M. & Crews, D. 1999 No threshold dose for estra-
R. R., Rubin, B. S., Talsness, C. E., Vandenbergh, J. G., diol-induced sex reversal of turtle embryos: how little is
Walser-Kuntz, D. R. & vom Saal, F. S. 2007a In vivo too much? Environ. Health Perspect. 107, 155-159.
effects of bisphenol A in laboratory rodent studies. (doi:10. 2307/3434373)
Reprod. Toxicol. 24, 199-224. (doi:10.1016/j.reprotox. Shultz, V. D., Phillips, S., Sar, M., Foster, P. M. & Gaido,
2007.06.004) K. W. 2001 Altered gene profiles in fetal rat testes after
Richter, C. A., Taylor, J. A., Ruhlen, R. R., Welshons, W. V. in utero exposure to di(w-butyl) phthalate. Toxicol Sci
& vom Saal, F. S. 2007¿> Estradiol and bisphenol A stimu-64, 233-242. (doi:10.1093/toxsci/64.2.233)
late androgen receptor and estrogen receptor gene Silva, M. J., Barr, D. B., Reidy, J. A., Malek, N. A., Hodge,
expression in fetal mouse prostate cells. Environ. Health C. C, Caudill, S. P., Brock, J. W, Needham, L. L. &
Perspect. 115, 902-908. Calafat, A. M. 2004 Urinary levels of seven
Rider, C. V., Furr, J., Wilson, V. S. & Gray Jr, L. E. 2008 A phthalate metabolites in the U.S. population from the
mixture of seven antiandrogens induces reproductive National Health and Nutrition Examination Survey
malformations in rats. Int. J. Androl 31 249-262. (NHANES) 1999-2000. Environ. Health Perspect. 112,
(doi:10.1111/j. 1365-2605. 2007. 00859.x) 331-338.
Ropero, A. B., Alonso-Magdalena, P., Garcia-Garcia, E., Sjödin, A., Carlsson, H., Thuresson, K., Sjölin, S.,
Ripoll, C, Fuentes, E. & Nadal, A. 2008 Bisphenol-A Bergman, À. & Ostman, C. 2001 Flame retardants in
disruption of the endocrine pancreas and blood glucose indoor air at an electronics recycling plant, and at other
homeostasis. Int. J. Androl. 31, 194-200. (doiilO.llll/ work environments. Environ. Sci Technol 35, 448-454.
J.1365-2605.2007.00832.X) (doi:10.1021/es000077n)
Rubin, B. S., Murray, M. K., Bamassa, D. A., King, J. C. Skakkebaek,
& N. E., Rajpert-De Meyts, E. & Main, K. M.
Soto, A. M. 2001 Perinatal exposure to low doses of 2001 Testicular dysgenesis syndrome: an increasingly
bisphenol A affects body weight, patterns of estrous cycli- common developmental disorder with environmental
city, and plasma LH levels. Environ. Health Perspect. 109, aspects. Hum. Reprod. 16, 972-978.
675-680. (doi: 10.2307/3454783) Skinner, M. K. & Anway, M. D. 2007 Epigenetic transge-
Rubin, B. S., Lenkowski, J. R., Schaeberle, C. M., nerational actions of vinclozolin on the development of
Vandenberg, L. N., Ronsheim, P. M. & Soto, A. M. disease and cancer. Crit. Rev. Oncog. 13, 75-82.
2006 Evidence of altered brain sexual differentiation in Soto, A. M., Vandenberg, L. N., Maffini, M. V. &
mice exposed perinatally to low, environmentally relevant Sonnenschein, C. 2008 Does breast cancer start in the
levels of bisphenol A. Endocrinology 147, 3681-3691. womb? toc C/m. Pharmacol Toxicol 102, 125-133.
(doi: 10.121 0/en.2006-0 1 89) Stoker, T. E., Laws, S. C, Crofton, K. M., Hedge, J. M.,
Rüssel, L. D., Ettlin, R. A., Sinha Hikkin, A. P. & Clegg, E. D. Ferrell, J. M. & Cooper, R. L. 2004 Assessment of DE-
1990 Histological and histopathological evaluation of the 71, a commercial polybrominated diphenyl ether
testis, pp. 210-266. Clearwater: Cache River Press. (PBDE) mixture, in the EDSP male and female pubertal
Sadeghian, H., Anand-Ivell, R., Baivers, M., Relan, V. & protocols. Toxicol. Sci 78, 144-155. (doi:10.1093/toxsci/
Ivell, R. 2005 Constitutive regulation of the Insl3 gene kfhO29)
in rat Leydig cells. Mol Cell Endocrinol 241, 10-20. Stoker, T E., Cooper, R. L., Lambright, C. S., Wilson, V S.,
(doi:10.1016/j.mce.2005.03.017) Furr, J. & Gray, L. E. 2005 In vivo and in vitro anti-andro-
Sakaue, M., Ohsako, S., Ishimura, R., Kurosawa, S., genic effects of DE-71, a commercial polybrominated
Kurohmaru, M., Hayashi, Y, Aoki, Y, Yonemoto, J. & diphenyl ether (PBDE) mixture. Toxicol Appi Pharmacol.
Tohyama, C. 2001 Bisphenol A affects spermatogenesis 207, 78-88. (doi:10.1016/j.taap.2005.05.010)
in the adult rat even at a low dose. J. Occup. Health 43, Sun, Y, Irie, M., Kishikawa, N., Wada, M., Kuroda, N. &
185-190. (doi:10.1539/joh.43.185) Nakashima, K. 2004 Determination of bisphenol A in

31.125.186.252 on Tue, 14 Nov 2023 19:46:37 +00:00
human breast milk by HPLC with column-switching and Viberg, H., Johansson, N., Fredriksson, A., Eriksson, J.,
fluorescence detection. Biomed. Chromatogr. 18, 501- Marsh, G. & Eriksson, P. 2006 Neonatal exposure to
507. (doi:10.1002/bmc.345) higher brominated diphenyl ethers, heptabromo-
Susiarjo, M., Hassold, T. J.5 Freeman, E. & Hunt, P. A. 2007 (PBDE 183), octabromo- (PBDE 203) or nonabromo-
Bisphenol A exposure in utero disrupts early oogénesis in diphenyl ether (PBDE 206), impairs spontaneous
the mouse. PLoS Genet. 3, 63-70. behaviour, and learning and memory functions of adult
Swan, S. H. et al. 2005 Decrease in anogenital distance mice. Toxicol. Sci. 92,211-218. (doi:10.1093/toxsci/kfjl96)
among male infants with prenatal phthalate exposure. Viberg, H., Mundy, W. & Eriksson, P. 2008 Neonatal
Environ. Health Perspect. 113, 1056-1061. (doi:10.1289/ exposure to decabrominated diphenyl ether (PBDE
ehp.8100) 209) results in changes in BDNF, CaMKII and GAP-
Takai, Y, Tsutsumi, O., Ikezuki, Y, Kamei, Y, Osuga, Y, 43, biochemical substrates of neuronal survival, growth,
Yano, T. & Taketan, Y 2000 Preimplantation exposure to and synaptogenesis. Neurotoxicology 29, 152-159.
bisphenol A advances postnatal development. Reprod. (doi:10.1016/j.neuro.2007.10.007)
Toxicol. 15,71-74. (doi:10.1016/S0890-6238(00)00119-2) vom Saal, F. S. & Hughes, C. 2005 An extensive new litera-
Takashima, K., Ito, Y, Gonzalez, F. J. & Nakajima, T. 2008 ture concerning low-dose effects of bisphenol A shows the
Different mechanisms of DEHP-induced hepatocellular need for a new risk assessment. Environ. Health Perspect.
adenoma tumorigenesis in wild-type and Ppara-nu'' 113, 926-933.
mice. J. Occup. Health 50, 169-180. (doi:10.1539/joh. vom Saal, F. S. & Myers, J. P. 2008 Bisphenol A and risk of
L7105) metabolic disorders. JAMA 300, 1353-1355. (doi:
Talsness, C. E., Shakibaei, M., Kuriyama, S. N., Grande, lO.lOOl/jama.300.11.1353)
S. W, Sterner-Kock, A., Schnitker, P., de Souza, C, vom Saal, F S. & Sheehan, D. M. 1998 Challenging risk
Grote, K. & Chahoud, I. 2005 Ultrastructural changes assessment. Forum Appl. Res. Public Pol. 13, 11-18.
observed in rat ovaries following in utero and lactational vom Saal, F. S., Cooke, P. S., Buchanan, D. L., Palanza, P.,
exposure to low doses of a polybrominated flame retard- Thayer, K. A., Nagel, S. C, Parmigiani, S. & Welshons,
ant. Toxicol. Lett. 157, 189-202. (doi:10.1016/j.toxlet. W. V. 1998 A physiologically based approach to the
2005.02.001) study of bisphenol A and other estrogenic chemicals on
Talsness, C. E., Kuriyama, S. N., Sterner-Kock, A., the size of reproductive organs, daily sperm production,
Schnitker, P., Grande, S. W., Shakibaei, M., Andrade, and behavior. Toxicol. Ind. Health 14, 239-260.
A., Grote, K. & Chahoud, I. 2008 In utero and lactational vom Saal, F. S. et al. 2007 Chapel Hill bisphenol A expert
exposures to low doses of polybrominated diphenyl ether- panel consensus statement: integration of mechanisms,
47 alter the reproductive system and thyroid gland of effects in animals and potential to impact human
female rat offspring. Environ. Health Perspect. 116, 308- health at current levels of exposure. Reprod. Toxicol. 24,
314. (doi:10.1289/ehp.l0536) 131-138.
Thomsen, C, Leknes, H., Lundanes, E. & Becher, G. 2002a Welshons, W V, Thayer, K. A., Judy, B. M., Taylor, J
A new method for determination of halogenated flame Curran, E. M. & vom Saal, F. S. 2003 Large effects
retardants in human milk using solid-phase extraction. from small exposures. I. Mechanisms for endocrine-dis-
J. Anal. Toxicol. 26, 129-137. rupting chemicals with estrogenic activity. Environ.
Thomsen, C, Lundanes, E. & Becher, G. 2002o Health Perspect. 111,994-1006.
Brominated flame retardants in archived serum Welshons,
samplesW. V, Nagel, S. C. & vom Saal, F. S. 2006 Large
from Norway: a study on temporal trends andeffects the rolefrom small exposures. III. Endocrine mechanisms
of age. Environ. Sci. Technol. 36, 1414-1418. (doi: mediating effects of bisphenol A at levels of human
10.1021/es0102282) exposure. Endocrinology 147(Suppl. 6), S56-S69.
Timms, B. G., Howdeshell, K. L., Barton, L., Bradley, S., Wetherill, Y B., Akingbemi, B. T., Kanno, J., McLachlan,
Richter, C. A. & vom Saal, F. S. 2005 Estrogenic chemi- J. A., Nadal, A., Sonnenschein, C, Watson, C. S.,
cals in plastic and oral contraceptives disrupt develop- Zoeller, R. T. & Belcher, S. M. 2007 In vitro molecular
ment of the mouse prostate and urethra. Proc. Nati mechanisms of bisphenol A action. Reprod. Toxicol. 24,
Acad. Sci. USA 102, 7014-7019. (doi:10.1073/pnas. 178-198. (doi:10.1016/j.reprotox.2007.05.010)
0502544102) Willhite, C. C, Ball, G. L. & McLellan, C. J. 2008
Tomonari, Y, Kurata, Y, David, R. M., Gans, G., Derivation of a bisphenol A oral reference dose (RfD)
Kawasuso, T & Katoh, M. 2006 Effect of di(2-ethyl- and drinking-water equivalent concentration. J. Toxicol.
hexyl) phthalate (DEHP) on genital organs from juvenile Environ. Health 11, 69-146.
common marmosets: I. Morphological and biochemical Wilson, V S., Lambright, C, Furr, J., Ostby, J., Wood, C,
investigation in 6 5 -week toxicity study. J. Toxicol. Held, G. & Gray, L. E. 2004 Phthalate ester-induced
Environ. Health A 69, 1651-1672. (doi: 10. 1080/1 52 gubernacular lesions are associated with reduced insl3
87390600630054) gene expression in the fetal rat testis. Toxicol. Lett. 146,
Vandenberg, L. N., Hauser, R., Marcus, M., Olea, N. & 207-215. (doi:10.1016/j.toxlet.2003.09.012)
Welshons, W. V. 2007 Human exposure to bisphenol A Yuan, J. et al 2008 Elevated serum polybrominated diphenyl
(BPA). Reprod. Toxicol. 24, 139-177. (doi:10.1016/ ethers and thyroid-stimulating hormone associated with
j.reprotox.2007.07.010) lymphocytic micronuclei in Chinese workers from an
Van der Ven, L. T. et al. 2008 Endocrine effects of tetrabro- E-waste dismantling site. Environ. Sci. Technol. 42,
mobisphenol-A (TBBPA) in Wistar rats as tested in a 2195-2200. (doi:10.1021/es702295f)
one-generation reproduction study and a subacute tox- Zhou, T, Ross, D. G., DeVito, M. J. & Crofton, K. M. 2001
icity study. Toxicology 245, 76-89. (doi:10.1016/j.tox. Effects of short-term in vivo exposure to polybrominated
2007.12.009) diphenyl ethers on thyroid hormones and hepatic enzyme
Viberg, H., Fredriksson, A. & Eriksson, P. 2003 Neonatal activities in weanling rats. Toxicol. Sci. 61, 76-82. (doi: 10.
exposure to polybrominated diphenyl ether (PBDE 153) 1093/toxsci/61.1.76)
disrupts spontaneous behaviour, impairs learning andZhou, T, Taylor, M. M., DeVito, M. J. & Crofton, K. M.
memory, and decreases hippocampal cholinergic recep- 2002 Developmental exposure to brominated diphenyl
tors in adult mice. Toxicol. Appi Pharmacol 192, ethers results in thyroid hormone disruption. Toxicol
95-106. (doi:10.1016/S0041-008X(03)00217-5) Sci. 66, 105-116. (doi:10.1093/toxsci/66.1.105)

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Components of Plastics Experimental Studies in Animals and Effects On Human Health

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Components of Plastic: Experimental Studies in Animals and Relevance for Human

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Components of plastic: experimental studies in

Components used in plastics, such as phthalates, bisphenol A (BPA), polybrominated dipheny

1. INTRODUCTION binding to receptors and hormone transport proteins

2079 This journal is © 2009 The Royal Society

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(d) Conclusions lengths of time depending on the product ( Joskow et al.

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consistent with reports of blood levels of unconjugated

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within the range of human exposure rather than the

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the bile (Kuester et al. 2007), TBBPA has been

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suppression of T3 induced tail shortenings indicating a (e) Exposure to PBDE

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in granulosa cells, which produce steroids and provide

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