NTP‐CERHR expert panel report on the reproductive and developmental toxicity of bisphenol A

The National Toxicology Program (NTP)1 established the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) in June 1998. The purpose of the CERHR is to provide timely, unbiased, scientifically sound evaluations of the potential for adverse effects on reproduction or development resulting from human exposures to substances in the environment. The NTP-CERHR is headquartered at NIEHS, Research Triangle Park, NC, and is staffed and administered by scientists and support personnel at NIEHS. Bisphenol A is a high-production volume chemical used in the production of epoxy resins, polyester resins, polysulfone resins, polyacrylate resins, polycarbonate plastics, and flame retardants. Polycarbonate plastics are used in food and drink packaging; resins are used as lacquers to coat metal products such as food cans, bottle tops, and water supply pipes. Some polymers used in dental sealants and tooth coatings contain bisphenol A. Exposure to the general population can occur through direct contact with bisphenol A or by exposure to food or drink that has been in contact with a material containing bisphenol A. CERHR selected bisphenol A for evaluation because of (1) high production volume; (2) widespread human exposure; (3) evidence of reproductive toxicity in laboratory animal studies; and (4) public concern for possible health effects from human exposures. Relevant literature on bisphenol A was identified from searches of the PubMed (Medline) and Toxline databases through February 2007 using the term “bisphenol” and the bisphenol A CAS RN (80-05-7). References were also identified from databases such as REPROTOX, HSDB, IRIS, and DART, from the bibliographies of the literature reviewed, by members of the expert panel, and in public comments. CERHR convened a 12-member, independent panel of government and non-government scientists to evaluate the scientific studies on the potential reproductive and developmental hazards of bisphenol A. The expert panel met publicly on March 5–7, 2007 and August 6–8, 2007. The Expert Panel Report on Bisphenol A is intended to (1) interpret the strength of scientific evidence that bisphenol A is a reproductive or developmental toxicant based on data from in vitro, animal, or human studies; (2) assess the extent of human exposures to include the general public, occupational groups, and other sub-populations; (3) provide objective and scientifically thorough assessments of the scientific evidence that adverse reproductive and developmental health effects may be associated with such exposures; and (4) identify knowledge gaps to help establish research and testing priorities to reduce uncertainties and increase confidence in future evaluations. This report has been reviewed by members of the expert panel and by CERHR staff scientists. Copies of this report have been provided to the CERHR Core Committee2 and will be made available to the public for comment. Following the public comment period, CERHR will prepare the NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Bisphenol A. This monograph will include the NTP Brief, the Expert Panel Report, and all public comments received on the Expert Panel Report. The NTP-CERHR Monograph will be made publicly available and transmitted to appropriate health and regulatory agencies. Reports can be obtained from the web site (http://cerhr.niehs.nih.gov) or from: Michael D. Shelby, PhD, NIEHS EC-32, PO Box 12233, Research Triangle Park, NC 27709. E-mail: [email protected] Section 1 is based initially on secondary review sources. Primary study reports are addressed by the Expert Panel if they contain information that is highly relevant for determining the effect of exposure on developmental or reproductive toxicity or if the studies were released subsequent to the reviews. The CAS RN for bisphenol A is 80-05-7. Synonyms for bisphenol A listed in Chem IDplus (ChemIDplus, 2006) include: 2-(4,4′-Dihydroxydiphenyl)propane; 2,2-Bis(4-hydroxyphenyl)propane; 2,2-Bis(hydroxyphenyl)propane; 2,2-Bis(p-hydroxyphenyl)propane; 2,2-Bis-4′-hydroxyfenylpropan [Czech]; 2,2-Di(4-hydroxyphenyl)propane; 2,2-Di(4-phenylol)propane; 4,4′-(1-Methylethylidene)bisphenol; 4,4′-Bisphenol A; 4,4′-Dihydroxydiphenyl-2,2-propane; 4,4′-Dihydroxydiphenyldimethylmethane; 4,4′-Dihydroxydiphenylpropane; 4,4′-Isopropylidene diphenol; 4,4′-Isopropylidenebisphenol; 4,4′-Isopropylidene diphenol; Biphenol A; Bis(4-hydroxyphenyl) dimethylmethane; Bis(4-hydroxyphenyl)dimethylmethane; Bis(4-hydroxyphenyl)propane; Bisferol A [Czech]; Bisphenol. Bisphenol A; DIAN; Diano; Dimethyl bis(p-hydroxyphenyl)methane; Dimethylbis(p-hydroxyphenyl)methane; Dimethylmethylene-p,p′-diphenol; Diphenylolpropane; Ipognox 88; Isopropylidenebis(4-hydroxybenzene); Parabis A, Phenol; (1-methylethylidene)bis-, Phenol; 4,4′-(1-methylethylidene)bis-; Phenol, 4,4′-dimethylmethylenedi-; Phenol, 4,4′-isopropylidenedi-; Pluracol 245, Propane; 2,2-bis(p-hydroxyphenyl)-; Rikabanol; Ucar bisphenol A; Ucar bisphenol HP; beta,beta′-Bis(p-hydroxyphenyl)propane; beta-Di-p-hydroxyphenylpropane; p,p′-Bisphenol A; p,p′-Dihydroxydiphenyldimethylmethane; p,p′-Dihydroxydiphenylpropane; p,p′-Isopropylidenebisphenol; and p,p′-Isopropylidenediphenol. Bisphenol A has a molecular mass of 228.29 g/mol and a molecular formula of C15H1602 (European-Union, 2003). The structure for bisphenol A is shown in Figure 1. Structure for bisphenol A. Bisphenol A is a white solid with a mild phenolic odor (European-Union, 2003). Physicochemical properties are listed in Table 1. Purity of bisphenol A was reported at 99–99.8%, and common impurities observed were phenol and ortho and para isomers of bisphenol A [reviewed in (European-Union, 2003)]. Terasaki et al. (2004) used reversed phase chromatography and nuclear magnetic resonance spectroscopy to characterize the composition of 5 commercial bisphenol A samples. The nominal purity of the samples was 97 or 98%. Actual purities were 95.3 to >99%. Up to 15 contaminants were identified among which were: 4-hydroxyacetophenone; 4,4′-(1,3-dimethylbutylidene) bisphenol; p-cumylphenol; 4-hydroxyphenyl isobutyl methyl ketone; 2,4*-dibhydroxy-2,2-diphenylpropane; 2,4′-dibhydroxy-2,2-diphenylpropane; 2,4-bis(4-hydroxycumyl)phenol; 2,3-dihydro-3-(4′-hydroxyphenyl)-1,1,3-trimethyl-1H-inden-5-ol; 2-(4′-hydroxyphenol)-2,2,4-trimethylchroman; and 4-(4′-hydroxyphenol)-2,2,4-trimethylchroman (Terasaki et al., 2005). No information on trade names for bisphenol A was located. Measurement of bisphenol A in environmental and biologic samples can be affected by contamination with bisphenol A in plastic laboratory ware and in reagents (Tsukioka et al., 2004; Völkel et al., 2005). Accuracy is also affected by measurement technique, particularly at the very low concentrations that can now be measured. Enzyme-linked immunosorbent assay (ELISA) has poor correlation with the LC-ECD method and also the different ELISA kits correlate poorly with each other. ELISA methods may overestimate bisphenol A in biologic samples due to lack of specificity of the antibody and effects of the biologic matrix (Inoue et al., 2002; Fukata et al., 2006). Although high performance liquid chromatography (HPLC) with ultraviolet, fluorescence, or electrochemical detection can be sensitive to concentrations <0.5 ng/ml (Sajiki et al., 1999; Inoue et al., 2000; Kuroda et al., 2003; Sun et al., 2004), these methods are unable to make definitive identification of bisphenol A or bisphenol A glucuronides, because similar retention times may occur for the metabolites of other endogenous and exogenous compounds (Völkel et al., 2005). Use of LC-mass spectrometry (MS) with and without hydrolysis of bisphenol A glucuronide permits determination of free and total bisphenol A with a limit of quantification of 0.1 for MS (Sajiki et al., 1999) and 1 μg/L for MS/MS (Völkel et al., 2005). Gas chromatography (GC)/MS has been used with solid phase extraction after treatment with glucuronidase and derivatization to measure total bisphenol A with a limit of detection of 0.05 μg/L for MS (Tan and Mohd, 2003) and 0.1 μg/L for MS/MS (Calafat et al., 2005). Some of the variability in studies cited in this and subsequent sections may be due to differences in measurement techniques and to contamination. Bisphenol A glucuronidate can be an unstable product that can be degraded in acidic and basic pH solutions and can be hydrolyzed to free bisphenol A at neutral pH and room temperature in diluted rodent urine, placental and fetal tissue homogenates at room temperature. However, conjugates in urine are stable for at least 7 days when stored at −4°C and at least 180 days when stored at −70°C (Waechter et al., 2007; Ye et al., 2007). Bisphenol A is manufactured by the acid catalyzed condensation of phenol and acetone (SRI, 2004). In 1998, members of the Society of the Plastics Industry Bisphenol A Task Group [assumed manufacturers of bisphenol A] included Aristech Chemical Corporation, Bayer Corporation, Dow Chemical Company, and Shell Chemical Company (Staples et al., 1998). Current manufacturers of bisphenol A in the U.S. are Bayer MaterialScience, Dow Chemical Company, General Electric, Hexion Specialty Chemicals, and Sunoco Chemicals (SRI, 2004) (S. Hentges, public comments, February 2, 2007). There are currently six bisphenol A and four polycarbonate plants in the U.S. (S. Hentges, personal communication, October 30, 2006); three of four polycarbonate plants are located within bisphenol A plants. In 2000, there were 13 epoxy plants in the U.S., but was not clear if all of the plants manufactured bisphenol A-containing epoxy resins. In mid-2004, U.S. bisphenol A production volume was reported at 1.024 million metric tons [∼2.3 billion pounds] (SRI, 2004). A production volume of 7.26 billion g [16 million pounds] was reported for bisphenol A in 1991 (reviewed in HSDB, 2003). United States bisphenol A consumption was reported at 856,000 metric tons [∼1.9 billion pounds] in 2003 (SRI, 2004); 2003 consumption patterns included 619,000 metric tons [∼1.4 billion pounds] used in polycarbonate resins, 184,000 metric tons [∼406 million pounds] used in epoxy resins, and 53,000 metric tons [∼117 million pounds] used in other applications. In 1999 and 2003, it was reported that most bisphenol A produced in the U.S. was used in the manufacture of polycarbonate and epoxy resins and other products [reviewed in (Staples et al., 1998; SRI, 2004)]. Polycarbonate plastics may be used in the manufacture of compact discs, "solid and multi wall sheet in glazing applications and film," food containers (e.g., milk, water, and infant bottles), and medical devices [reviewed in (European-Union, 2003)]. Bisphenol A may have been used at one time in Europe in polyvinyl chloride cling film and plastic bags, but that use is believed to have been discontinued (European Food Safety Authority, 2006). Contact with drinking water may occur through the use of polycarbonate for water pipes and epoxy-phenolic resins in surface coatings of drinking water storage tanks [reviewed by (European Food Safety Authority, 2006)]. Polycarbonate blends have been used to manufacture injected molded parts utilized in alarms, mobile phone housings, coil cores, displays, computer parts, household electrical equipment, lamp fittings, and power plugs. Automotive and related uses for polycarbonate blends include light reflectors and coverings, bumpers, radiator and ventilation grills, safety glazing, inside lights, and motorcycle shields and helmets. Epoxy resins are used in protective coatings, structural composites, electrical laminates, electrical applications, and adhesives. The European Union (2003) reported that smaller volumes of bisphenol A are used in production of phenoplast, phenolic, and unsaturated polyester resins, epoxy can coatings, polyvinyl chloride (PVC) plastic, alkoxylated bisphenol A, thermal paper, and polyols/polyurethane. Other uses reported for products manufactured from bisphenol A included protective window glazing, building materials, optical lenses, and development of dyes [reviewed in (Staples et al., 1998)]. A search of the National Library of Medicine Household Products Database (NLM, 2006) revealed that bisphenol A-based polymers are used in coatings, adhesives, and putties available to the general pubic for use in automobiles, home maintenance and repair, and hobbies, but only 3 epoxy products, used for crafts and hobbies, contain bisphenol A itself. Some polymers manufactured with bisphenol A are Food and Drug Administration (FDA)-approved for use in direct and indirect food additives and in dental materials, as reported in the Code of Federal Regulations (CFR) (FDA, 2006). In the CFR, bisphenol A is often referred to as 4,4′-isopropylidnediphenol. Polymers manufactured with bisphenol A are FDA-approved for use as anoxomers and in coatings, adhesives, single and repeated food contact surfaces, and tooth shade resin materials. The European Union (2003) noted that resins, polycarbonate plastics, and other products manufactured from bisphenol A can contain trace amounts of residual monomer and additional monomer may be generated during breakdown of polymer. The American Plastics Council reports that residual bisphenol A concentrations in polycarbonate plastics and epoxy resins are generally <50 ppm (S. Hentges, personal communication, October 30, 2006). Polymer hydrolysis can occur at elevated temperature or extreme pH. An example of potential human exposure is migration of bisphenol A from a food container into the food. Exposure to bisphenol A through food is discussed in detail in Section 1.2.3.2. Bisphenol A may be present in the environment as a result of direct releases from manufacturing or processing facilities, fugitive emission during processing and handling, or release of unreacted monomer from products (European-Union, 2003). According to the Toxics Release Inventory database, total environmental release of bisphenol A in 2004 was 181,768 pounds, with releases of 132,256 pounds to air, 3533 pounds to water, 172 pounds to underground injection, and 45,807 pounds to land 2004). Bisphenol A released to the is degraded by (European-Union, 2003). for the bisphenol A and was at was also noted that and of bisphenol A in the is possible and of were [reviewed in (Staples et al., 1998; 2003)]. The European Union (2003) noted that because of low and in the bisphenol A is not to the in by and in water were to be of in the bisphenol A is to be from emission on and the European Union (2003) and et al. that bisphenol A is of low and not to be from water through that hydrolysis of bisphenol A in water is However, there was on potential for of bisphenol A in on and chemical the European Union that of bisphenol A in water is et al. noted that bisphenol A is to in a basic it was that from surface water is on such as and of bisphenol A in water was at to days [reviewed in (Staples et al., 1998)]. of bisphenol A from water was reported in the of studies reviewed by the European Union (2003) and et al. A of days was reported in a study bisphenol A concentrations in surface the of a bisphenol A [reviewed in (Staples et al., 1998)]. the et al. review was not been but were at on such the European Union (2003) and et al. that bisphenol A to or be or on data for of bisphenol A in water, the European Union (2003) that bisphenol A be degraded in and a of days for of bisphenol A in to the et al. and European Union (2003) a study of A in through laboratory and was released by et al. In that A was and not in different within 3 were at and based on the study that bisphenol A has low in The study that bisphenol A is not to be or from In studies reviewed by the European Union (2003) and et al. for were at and were to be from the that potential for of bisphenol A is low in were for [reviewed in (European-Union, 2003)]. studies exposures in in the U.S. used to measure bisphenol A concentrations in environmental et al., 2003, 2006). In the study et al., bisphenol A concentrations were in and the of Bisphenol A was in of 13 samples at at at In from and bisphenol A was in of 13 samples at at at bisphenol A was in all of 13 samples of at of ppm and at of ppm In the study et al., bisphenol A concentrations were inside and at least and Bisphenol A was in of samples from each concentrations from at concentrations of In samples from and bisphenol A was in 3 of samples at concentrations of In study using a technique, bisphenol A concentrations in from U.S. were et al., 2003). bisphenol A in in this study was with of samples the information is available for bisphenol A concentrations in U.S. water In bisphenol A concentrations were reported at μg/L in surface water samples 1 bisphenol A production site but bisphenol A was not in surface water of 7 bisphenol A production in the U.S. (Staples et al., Bisphenol A was at a samples with bisphenol A the limit of of μg/L and a of μg/L in of samples from U.S. in 1999 and In and bisphenol A was not in from a treatment in and concentrations were not limit not in samples from surface in and in drinking water at of treatment at plants in and et al., 2003). In water samples in Europe and from the through bisphenol A concentrations were μg/L and in most were μg/L [reviewed in (European-Union, 2003)]. The European Union (2003) noted that the potential for human exposure to bisphenol A is through products that contact food. of food contact that can contain bisphenol A include food and containers with epoxy resin coatings and polycarbonate and such as used to In to commercial food et al. reported a bisphenol A of μg/L from a in from Bisphenol A was after hydrolysis of Ye et al. concentrations of bisphenol A in samples from of bisphenol A was in samples from The total bisphenol in was μg/L to The free bisphenol A was μg/L to Sun et al. (2004) used an method to measure bisphenol A concentrations in from Bisphenol A concentrations from and the was reported at No were observed bisphenol A and concentrations in from samples were to and samples reported in a study by Kuroda et al. Bisphenol A were in milk, and the was reported at Bisphenol A in were to in was not clear and samples were obtained from the in the have migration of bisphenol A from polycarbonate infant or containers into or food of studies are in Table for bisphenol A were by or The European Union (2003) noted that in bisphenol A concentrations were the detection limit in food bisphenol A was concentrations were μg/L in to infant and in to polycarbonate An is one study that reported bisphenol A concentrations at to μg/L in a food and μg/L in a et al., 2005). In the of were and the study that bisphenol A have from the Expert Panel that were at or for not for use of study with infant food and reported bisphenol A et al., Some studies the effects of repeated use of polycarbonate noted of bisphenol A with repeated use 2000; et al., 2003; 2004). was that the increase in bisphenol A migration was by to the during from other reports that of bisphenol A with repeated and it was that available bisphenol A was present at the surface of the product and by et al., et al., 1999; et al., 2002; European 2003). study et al., 1999) concentrations of bisphenol A in to products that been because of residual concentrations of bisphenol A and other The study by et al. that infant to or at for bisphenol A at concentrations residual monomer and it was that hydrolysis of the molecular bisphenol A-based epoxy resins are used as protective in for food and and may be used in storage (European-Union, 2003). bisphenol A monomer can from the coatings to or within were to measure concentrations of bisphenol A in available or to measure concentrations of bisphenol A from can into food the measurement of bisphenol A concentrations in the most the CERHR review will on with will not be reviewed, with the of one study by et al. that was by the in of bisphenol A Bisphenol A concentrations in infant are in Table and bisphenol A concentrations in are in Table the of in which bisphenol A concentrations were at to most were 0.1 The European Union also noted an extraction study with an epoxy resin that is used to on that a of bisphenol A in was The European Union noted that the a very exposure but to use that in because other was Expert Panel that a study of bisphenol A in and 2006) identified a of μg/L In one were with milk, or et al., 2004). The were at or and at 1 or days or or the to each were was that of the bisphenol A to food after and that bisphenol A concentrations not during storage or as a result of The study that most migration during can the or to not increase migration of bisphenol A, but that to with of et al. (2003) the effects of of and on migration of bisphenol A from In with water, to to migration of bisphenol A but the of to with water, amounts of bisphenol A from with or and to et al. reported of bisphenol A from into water when the were to A study exposures of U.S. bisphenol A concentrations in liquid food and solid food to the at home and at et al., 2003). of food to were a were on four liquid food samples and four solid food samples from the and liquid food samples and solid food samples from Bisphenol A was in all solid food three liquid food samples from the and liquid food samples from the of bisphenol A from in liquid and from in solid food. The study exposures of U.S. was repeated with a and bisphenol A concentrations in liquid food and solid food to the at home and at et al., 2006). Bisphenol A concentrations were by in food a to at least at home and at Bisphenol A was in of solid food concentrations were reported at to to of liquid food concentrations of bisphenol A; concentrations were reported at in liquid food. were also for of at and at Bisphenol A was in of concentrations from