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BPA

BPA

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263
Review ARticle
Critical evaluation of key evidence on the human healthhazards of exposure to bisphenol A
J. G. Hengstler,
1
H. Foth,
2
. Gebel,
3
P.-J. Kramer,
4
W. Lilienblum,
5
H. Schweinurth,
6
W. Völkel,
7
 K.-M. Wollin,
8
and U. Gundert-Remy 
9
1
Leibniz Research Centre for Working Environment and Human Factors (IfADo), University of Dortmund, Dortmund,Germany,
2
Institute of Environmental Toxicology, University of Halle, Halle/Saale, Germany,
3
Federal Institute for Occupational Safety and Health, Dortmund, Germany,
4
Research and Development, Merck Serono, Darmstadt,Germany,
Dr. Lilienblum Consulting Toxicology LiCoTox, Hemmingen/Han, Germany,
Global Early Development,Bayer Schering Pharma AG, Berlin, Germany,
Bavarian Health and Food Safety Authority, Munich, Germany,
8
Lower Saxony Governmental Institute of Public Health, Hannover, Germany, and 
9
Federal Institute for Risk Assessment (BfR),Berlin, Germany 
Absra
Despite the act that more than 5000 saety-related studies have been published on bisphenol A (BPA), there seemsto be no resolution o the apparently deadlocked controversy as to whether exposure o the general populationto BPA causes adverse eects due to its estrogenicity. Thereore, the Advisory Committee o the German Society o  Toxicology reviewed the background and cutting-edge topics o this BPA controversy. The current tolerable dailyintake value (TDI) o 0.05 mg/kg body weight [bw]/day, derived by the European Food Saety Authority (EFSA), ismainly based on body weight changes in two- and three-generation studies in mice and rats. Recently, these studiesand the derivation o the TDI have been criticized. Ater having careully considered all arguments, the Committeehad to conclude that the criticism was scientifcally not justifed; moreover, recently published additional data urthersupport the reliability o the two- and three-generation studies demonstrating a lack o estrogen-dependent eectsat and below doses on which the current TDI is based. A requently discussed topic is whether doses below 5 mg/kg bw/day may cause adverse health eects in laboratory animals. Meanwhile, it has become clear that positiveresults rom some explorative studies have not been confrmed in subsequent studies with higher numbers o animals or a priori defned hypotheses. Particularly relevant are some recent studies with negative outcomes thataddressed eects o BPA on the brain, behavior, and the prostate in rodents or extrapolation to the human situation. The Committee came to the conclusion that rodent data can well be used as a basis or human risk evaluation.Currently published conjectures that rats are insensitive to estrogens compared to humans can be reuted. Datarom toxicokinetics studies show that the hal-lie o BPA in adult human subjects is less than 2 hours and BPA iscompletely recovered in urine as BPA-conjugates. Tissue deconjugation o BPA-glucuronide and -sulate may occur.Because o the extremely low quantities, it is only o minor relevance or BPA toxicity. Biomonitoring studies havebeen used to estimate human BPA exposure and show that the daily intake o BPA is ar below the TDI or the generalpopulation. Further topics addressed in this article include reasons why some studies on BPA are not reproducible;the relevance o oral versus non-oral exposure routes; the degree to which newborns are at higher systemic BPAexposure; increased BPA exposure by inusions in intensive care units; mechanisms o action other than estrogenreceptor activation; and the current regulatory status in Europe, as well as in the USA, Canada, Japan, New Zealand,and Australia. Overall, the Committee concluded that the current TDI or BPA is adequately justifed and that theavailable evidence indicates that BPA exposure represents no noteworthy risk to the health o the human population,including newborns and babies.
Kyords:
Biomonitoring, endocrine disruption, estrogenic eects, intensive care units, interspecies extrapolation,low-dose eects, regulation, three- and two-generation studies, tissue deconjugation, tolerable daily intake,toxicokinetic modeling
 Address for Correspondence
: J. G. Hengstler, Leibniz Research Centre or Working Environment and Human Factors (IADo), University o Dortmund, Ardeystrasse 67, 44139 Dortmund, Germany. E-mail: hengstler@iado.de; U. Gundert-Remy, Federal Institute or Risk  Assessment (BR), 14195 Berlin, Germany. E-mail: gundert@googlemail.com
(Received 05 November 2010; revised 19 January 2011; accepted 25 January 2011)
Critical Reviews in Toxicology 
, 2011; 41(4): 263–291Copyright © 2011 Inorma Healthcare USA, Inc.ISSN 1040-8444 print/ISSN 1547-6898 onlineDOI: 10.3109/10408444.2011.558487
   C  r   i   t   i  c  a   l   R  e  v   i  e  w  s   i  n   T  o  x   i  c  o   l  o  g  y   D  o  w  n   l  o  a   d  e   d   f  r  o  m    i  n   f  o  r  m  a   h  e  a   l   t   h  c  a  r  e .  c  o  m    b  y   C  a  r  r   i  e   B  a  r  c   l  a  y  o  n   0   3   /   2   9   /   1   1   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .
 
264 J. G. Hengstler et al.
conns
 Abstract ...................................................................................................................................................................................263Introduction ............................................................................................................................................................................264Derivation o tolerable daily intake values ...........................................................................................................................265 Are the three-and two-generation studies o yl et al. valid?..............................................................................................265Do oral low BPA doses below 5 mg/kg bw/day cause adverse health eects in laboratory animals? .............................267How can dierences between industry sponsored and publicly sponsored studies be explained? ...............................270oxicokinetics .........................................................................................................................................................................271Humans ...................................................................................................................................................................................271Non-human primates ............................................................................................................................................................275Rats ..........................................................................................................................................................................................275Mice .........................................................................................................................................................................................275Importance o the exposure route .........................................................................................................................................275Can rodents be used to extrapolate to the human situation with respect to estrogenic activity? ....................................276 Are there susceptible subpopulations? .................................................................................................................................277oxicokinetics in children ......................................................................................................................................................277oxicokinetics in other groups ..............................................................................................................................................278issue deconjugation o BPA-glucuronide and BPA-sulate ...............................................................................................278oxicodynamics ......................................................................................................................................................................279Specic exposure conditions ................................................................................................................................................279Neonatal intensive care unit ..................................................................................................................................................279Polycarbonate (PC) bottles ....................................................................................................................................................279How can biomonitoring support risk evaluation? ...............................................................................................................280Results and interpretation o biomonitoring studies with BPA ..........................................................................................280Biomonitoring and exposure assessment ............................................................................................................................281 What are the mechanisms o action o BPA? Does the multitude o mechanisms besides estrogen receptor activationmake the substance more hazardous? ..................................................................................................................................282Epidemiological studies in the general population .............................................................................................................283Recent governmental responses ...........................................................................................................................................283European Union .....................................................................................................................................................................283Denmark .................................................................................................................................................................................284France ......................................................................................................................................................................................284Switzerland .............................................................................................................................................................................284 Australia and New Zealand....................................................................................................................................................284Canada ....................................................................................................................................................................................285USA ..........................................................................................................................................................................................285Japan ........................................................................................................................................................................................285 Acknowledgments ..................................................................................................................................................................285Declaration o interest ............................................................................................................................................................286Reerences ...............................................................................................................................................................................286
inroduon
For more than 10 years there has been a scientic and journalistic controversy whether bisphenol A (BPA)causes adverse eects in humans related to its estro-genic activity (Borrell, 2010; Lorentzen and Hattan,2010; Aschberger et al., 2010; aylor et al., 2010; Yanget al., 2009). BPA, a building block o polycarbonateplastic and epoxy resins, was rst synthesized in 1891.However, commercial production did not begin beorethe early 1950s when the rst epoxy resins were devel-oped (Vogel, 2009). Epoxy resins are extensively used asprotective coatings on metal equipment, ood cans, pip-ing, and dental sealants. In 1957, it was discovered thatpolymerization o BPA with phosgene leads to polycar-bonate. Tere is an unusual wealth o saety-related stud-ies carried out on BPA. Tese cover nearly every possibleendpoint. Its estrogenic properties were described asearly as 1936 (Dodds and Lawson, 1936). o date, morethan 5000 studies on BPA have been published. It is obvi-ous that this should be enough inormation to resolvethe controversy, but nevertheless this has not yet beenachieved and those not directly involved in BPA researchare usually puzzled by the never-ending and sometimesemotional debate. In order to contribute to a balancedand well-ounded resolution o the seemingly dead-locked situation, the Advisory Committee o the German
   C  r   i   t   i  c  a   l   R  e  v   i  e  w  s   i  n   T  o  x   i  c  o   l  o  g  y   D  o  w  n   l  o  a   d  e   d   f  r  o  m    i  n   f  o  r  m  a   h  e  a   l   t   h  c  a  r  e .  c  o  m    b  y   C  a  r  r   i  e   B  a  r  c   l  a  y  o  n   0   3   /   2   9   /   1   1   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .
 
Bisphenol A 265
Society o oxicology 
1
reviewed the background and thecutting-edge questions o the BPA controversy (able 1)and oers an independent judgement.
Draon o orab day nak aus
BPA has been tested in subchronic oral toxicity studiesusing rats, mice, and dogs (US EPA, 1984 a, 1984b, 1984c;NP, 1982). Rats and mice were administered BPA in thediet or 90 days (250–4000 ppm in rats; 5000–25,000 ppmin mice) (NP, 1982). Doses higher than 1000 ppm (equiv-alent to approximately 67 mg/kg/day) lead to decreasedbody weight in both sexes o rats. In dogs (90 days; 1000–9000 ppm BPA in the diet), the only toxic eect observed was an increase in mean liver weight in the high-dosegroup (US EPA, 1984a). Bisphenol A was evaluated ordevelopmental toxicity in CD rats (0, 160, 320, or 640 mg/kg bw/day) and CD-1 mice (0, 500, 750, 1000, or 1250 mg/kg bw/day) dosed daily by gastric intubation rom gesta-tional days 6 through 15. In Charles River rats, the only eect observed in two-generation studies (100–9000 ppmBPA in the diet) was decreased body weight in the F0generation at 9000 ppm and in the F1 generation at dosesequal or higher than 1000 ppm (US EPA, 1984b, 1984c). Also, male mice receiving doses higher than 15,000 ppmand the exposed emales exhibited a decreased body  weight gain compared to the controls (in mice 15,000 ppmis equivalent to approximately 1950 mg/kg/day based on aood actor o 0.13). In mice, doses o 1250 mg/kg/day ledto maternal toxicity, including etotoxic eects. However,no signicant increase in the incidence o malormations was observed (NP, 1985). In rats, doses equal to andhigher than 1280 mg/kg/day were not toxic and did notcause malormations o the etus (NP, 1986).aken together, the toxic eects observed in labora-tory animals ater repeated BPA exposure occur at dosesthat are several magnitudes higher than the exposure o the general human population. Since it is not clear to which extent these rather early studies mentioned aboveaccounted or internal quality assurance and were con-ducted according to accepted modern testing guidelines(or elements o them), their validity, reliability, and thus value or hazard and risk assessment are consideredlimited. Modern testing guidelines represent interna-tionally agreed-upon guidance with the goal to providea reproducible set o data that can optimally satisy allinternationally agreed saety assessment criteria used inthe regulatory processes. Hence, the ocus o this articleis on ndings o more recent studies conducted or regu-latory purposes.In a three-generation rat study (yl et al., 2002) and atwo-generation study in mice (yl et al., 2008b, 2008c),BPA was ound to decrease body weight, and the weightso the livers and kidneys. An overall no observed adverseeect level (NOAEL) o 5 mg BPA/kg bw/day was derived,based on liver weight decreases, the most sensitive end-point. At doses leading to liver weight changes, BPA didnot cause any eects on hormone-sensitive endpoints, which are the ocus o concern o the current debate onBPA toxicity. Using an uncertainty actor o 100 (10 orinterspecies dierences, 10 or interindividual dier-ences), a tolerable daily intake (DI) o 0.05 mg/kg bw/day was set by the European Food Saety Authority (EFSA,2006) and conrmed in 2008 and 2010 (EFSA, 2008, 2010).Tis DI has been accepted by most regulatory agencies worldwide. Similarly, the United States EnvironmentalProtection Agency (US EPA) derived a reerence dose o 0.05 mg/kg bw/day (reviewed by Willhite et al., 2008).Perhaps the most intensively currently discussed topic is whether the NOAELs used or deriving the DI are scien-tically valid and appropriate or risk assessment.
Ar h hr- and o-gnraon suds o ty  a. ad?
Te studies o yl et al. (2002, 2008b, 2008c) did notreveal any eects on ertility or development. Doses o 0.001, 0.02, 0.3, 5, 50, and 500 mg/kg bw/day o BPA weretested in CD Sprague-Dawley rats in a three-generationstudy (yl et al., 2002), and 0.003, 0.03, 0.3, 5, 50, as wellas 600 mg BPA/kg bw/day in CD-1 mice in a two-gen-eration study (yl et al., 2008b). Te dose ranges in thelatter studies also cover the “low-dose range.” Anothertwo-generation reproductive toxicity study perormedunder good laboratory practice (GLP) did also not
able 1. Cutting edge topics o the current controversy on BPA. Are the studies used or regulatory purposes awed?Do oral low doses below 5 mg/kg bw/day cause adverse healtheects in laboratory animals?How can dierences between industry sponsored and publicly sponsored studies be explained?Swallow or inject? What is the relevance o the oral route versusimplantation o pumps or intravenous injection?Can rodents be used to extrapolate to the human situation?o which degree are embryos, babies, or children moresusceptible?How critical is exposure by intravenous inusion in intensive careunits?How critical is tissue deconjugation o BPA-glucuronide andBPA-sulate?How can biomonitoring support risk evaluation? What are the mechanisms o action o BPA? Does the multitudeo mechanisms other than estrogen receptor activation make thesubstance more dangerous? Why are recent governmental responses inconsistent?
1
Te Advisory Committee o the German Society o oxicology iselected by the members o the German Society o oxicology andconsists o representatives rom academia, industry, and administra-tion in order to guarantee a broad range o toxicological competence.Te Advisory Committee may consult urther experts with expertise inspecic elds o oxicology. In case o the present work, the commit-tee included Dr. Wolgang Völkel as an additional expert and sent themanuscript to Wolgang Dekant, and Regine Kahl or discussion. Te Advisory Committee presents and justies its activities to the memberso the German Society o oxicology, or example at the yearly plenary meeting. Te German Society o oxicology is the largest scientic toxi-cological organization in Europe, with more than 1000 members..
   C  r   i   t   i  c  a   l   R  e  v   i  e  w  s   i  n   T  o  x   i  c  o   l  o  g  y   D  o  w  n   l  o  a   d  e   d   f  r  o  m    i  n   f  o  r  m  a   h  e  a   l   t   h  c  a  r  e .  c  o  m    b  y   C  a  r  r   i  e   B  a  r  c   l  a  y  o  n   0   3   /   2   9   /   1   1   F  o  r  p  e  r  s  o  n  a   l  u  s  e  o  n   l  y .

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