Monograph on the Potential Human Reproductive and ... - OEHHA

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BISPHENOL A Table 21 Saliva and Urinary Concentrations of Total Bisphenol A in Adults Receiving Dental Sealants a Mean7SD bisphenol A concentration (ng/mL) b Collection time Both sealants Delton LC Helioseal F Saliva Pretreatment 0.3070.17 0.3470.19 0.2270.03 Immediately after treatment 26.5730.7 42.8728.9 0.5470.45 1 hr post-treatment 5.12710.7 7.86712.73 0.2170.03 Urine (creatinine-adjusted) Pretreatment 2.4171.24 2.671.4 2.1270.93 1 hr post-treatment 20.1733.1 27.3739.1 7.26713.5 24 hr post-treatment 5.1473.96 7.3473.81 2.0671.04 a Joskow et al. (2006). b Samples were treated with b-glucuronidase. sealants. Excluded from the study were individuals with resin-based materials on their teeth, smokers, users of antihistamines, and patients with Gilbert syndrome. The volunteers received either Helioseal F (n 5 5) or Delton LC (n 5 9) sealant. Sealant was weighed before and after application to determine the amount applied, and the number of treated teeth was recorded. The mean number of teeth treated was 6/person and the mean total weight of sealant applied was 40.35 mg/person. In a comparison of the 2 sealants, no differences were reported for number of teeth treated or amount of sealant applied. Saliva samples were collected before treatment, immediately after, and at 1 hr following sealant application. Urine samples were collected before treatment and at 1 and 24 hr following sealant placement. A total of 14–15 saliva samples and 12–14 urine samples were collected at each time point. Samples were treated with b-glucuronidase and analyzed for bisphenol A concentrations using selective and sensitive isotope-dilution-MS-based methods. Table 21 summarizes changes in saliva and bisphenol A concentrations. Immediately and at 1 hr after sealant application, salivary concentrations of bisphenol A compared to baseline were significantly higher in the patients who received the Delton LC sealant. Bisphenol A concentrations in saliva increased 484-fold following application of the Delton LC sealant. Urinary concentrations of bisphenol A were increased 1 hr following application of the Delton LC sealant. Concentrations of bisphenol A in saliva and urine following application of Helioseal F were reported to be similar to baseline. The European Union (2003) reviewed unpublished preliminary data from a human dermal absorption study. Skin samples obtained from 3 human donors (6 samples/ donor/dose) were exposed to 5 or 50 mg/cm 2 (3.18 or 31.8 mg/mL) 14 C-bisphenol A in ethanol vehicle. Following evaporation of the vehicle, bisphenol A was resuspended in artificial sweat. Radioactivity was measured in receptor fluid at various time intervals over a 24hr period. Radioactivity was measured in the stratum corneum and ‘‘lower’’ skin layer at 24 hr. Authors of the European Union report noted that tritiated water was not used as a marker for skin integrity. However, based on the patterns of results, they concluded that skin integrity was likely lost after 4–8 hr. The European Union authors therefore concluded that the only reliable data from the study were those for the cumulative percentage of the dose in receptor fluid at 8 hr, which was reported at 0.57– Birth Defects Research (Part B) 83:157–395, 2008 183 1.22% at 5 mg/cm 2 and 0.491–0.835% at 50 mg/cm 2 . Because radioactivity in skin was not measured at 8 hr, the percentage of the applied dose remaining on skin and available for future absorption could not be determined. Based on ratios of receptor fluid concentrations and lower skin levels (1:2 to 1:8) at 24 hr, and assuming that the higher ratio applies to skin at 8 hr, the authors of the European Union report predicted that 10% of the dose would be present in ‘‘lower’’ skin layers. Therefore, dermal absorption of bisphenol A was estimated at 10%. 2.1.1.2 Distribution: In humans, bisphenol A was measured in cord blood and amniotic fluid, demonstrating distribution to the embryo or fetus. Studies reporting bisphenol A concentrations in fetal and/or maternal compartments are summarized in Table 9. Detailed descriptions of those studies are also presented below. Engel et al. (2006) reported concentrations of bisphenol A in human amniotic fluid. Twenty-one samples were obtained during amniocentesis conducted before 20 weeks gestation in women who were referred to a U.S. medical center for advanced maternal age. Bisphenol A concentrations in amniotic fluid were measured using LC with electrochemical detection. Bisphenol A was detected in 10% of samples at concentrations exceeding the LOD (0.5 mg/L). Bisphenol A concentration ranges of 0.5– 1.96 mg/L were reported. Schönfelder et al. (2002b) examined bisphenol A concentrations in maternal and fetal blood and compared bisphenol A concentrations in blood of male and female fetuses. In a study conducted at a German medical center, blood samples were obtained from 37 Caucasian women between 32–41 weeks gestation. At parturition, blood was collected from the umbilical vein after expulsion of the placenta. Bisphenol A concentrations in plasma were measured by GC/MS. Control experiments were conducted to verify that bisphenol A did not leach from collection, storage, or testing equipment. Bisphenol A was detected in all samples tested, and concentrations measured in maternal and fetal blood are summarized in Table 9. Mean bisphenol A concentrations were higher in maternal (4.473.9 [SD] mg/L) than fetal blood (2.972.5 mg/L). Study authors noted that in 14 cases fetal bisphenol A plasma concentrations exceeded those detected in maternal plasma. Among those 14 cases, 12 fetuses were male. Analysis by paired t-test showed significantly higher mean bisphenol A concentrations in the blood of male than female
184 CHAPIN ET AL. fetuses (3.572.7 vs. 1.771.5 ng/mL, P 5 0.016). Bisphenol A concentrations were measured in placenta samples at 1.0–104.9 mg/kg. Ikezuki et al. (2002) measured concentrations of bisphenol A in serum from 30 healthy premenopausal women, 37 women in early pregnancy, 37 women in late pregnancy, and 32 umbilical cord blood samples. Concentrations of bisphenol A were also measured in 32 samples of amniotic fluid obtained during weeks 15–18 of gestation, 38 samples of amniotic fluid obtained at fullterm cesarean section, and 36 samples of ovarian follicular fluid collected during in vitro fertilization procedures. [It was not stated if different sample types were obtained from the same subjects.] An ELISA method was used to measure bisphenol A concentrations and results were verified by HPLC. The mean7SD concentration of bisphenol A in follicular fluid was reported at 2.470.8 mg/L. As summarized in Table 7 for nonpregnant women and Table 9 for maternal and fetal samples, concentrations of bisphenol A in follicular fluid were similar to those detected in the serum of fetuses and pregnant and non-pregnant women and in amniotic fluid collected in late pregnancy (B1–2 mg/L). Bisphenol A concentrations in amniotic fluid samples collected in early pregnancy were B5-fold higher than in other samples, and the difference achieved statistical significance (Po0.0001). Study authors postulated that the higher concentrations of bisphenol A in amniotic fluid collected during gestation weeks 15–18 may have resulted from immature fetal liver function. They noted that according to unpublished data from their laboratory, the percentage of glucuronidated bisphenol A in midterm amniotic fluid was B34%, which is much lower than reported values for other human fluids (490%). Yamada et al. (2002) measured bisphenol A concentrations in maternal serum and amniotic fluid from Japanese women. Samples were collected between 1989–1998 in women undergoing amniocentesis around gestation week 16. One group of samples was obtained from 200 women carrying fetuses with normal karyotypes, and a second group of samples was obtained from 48 women carrying fetuses with abnormal karyotypes. An ELISA method was used to measure bisphenol A concentrations. [As discussed in Section 1.1.5, ELISA may overestimate bisphenol A.] Concentrations of bisphenol A measured in maternal plasma and amniotic fluid are summarized in Table 9. Median concentrations of bisphenol A in maternal serum (B2–3 mg/L) were significantly higher [B10-fold] than concentrations in amniotic fluid (B0–0.26 mg/L) in the groups carrying fetuses with normal and abnormal karyotypes. However, in 8 samples from women carrying fetuses with normal karyotypes, high concentrations (2.80–5.62 mg/L) of bisphenol A were measured in amniotic fluid. The study authors interpreted the data as indicating that bisphenol A does not accumulate in amniotic fluid in most cases but accumulation is possible in some individuals. Bisphenol A concentrations in maternal blood were significantly higher [by B33%] in woman carrying fetuses with abnormal versus normal karyotypes. However, the study authors noted that the effect may not be related to bisphenol A exposure because there was no adjustment for maternal age, and concentrations in amniotic fluid did not differ between groups. In the group carrying fetuses with normal karyotypes, data obtained from 1989–1998 were summarized by year. Median bisphenol A concentrations in serum significantly decreased over that time from a concentration of 5.62 mg/L detected in 1989 to 0.99 mg/L in 1998. Kuroda et al. (2003) used an HPLC method to measure bisphenol A concentrations in 9 sets of maternal and cord blood samples obtained from Japanese patients at the time of delivery. Bisphenol A concentrations were also measured in 21 sets of serum and ascitic fluid samples collected from sterile Japanese patients of unspecified sexes and ages. Results for pregnant women are summarized in Table 9. Mean7SD concentrations of bisphenol A were lower in maternal (0.4670.20 ppb [lg/ L]) than cord blood (0.6270.13 ppb [lg/L]). There was a weak positive correlation (r 5 0.626) between bisphenol A concentrations in maternal and cord blood. Concentrations of bisphenol A in the blood of sterile patients are summarized Table 7. There were no differences between pregnant and non-pregnant blood levels (Kuroda et al., 2003). Mean7SD concentrations of bisphenol A were higher in ascitic fluid (0.5670.19 ppb [lg/L]) than in serum (0.4670.20 ppb [lg/L]). The correlation between bisphenol A concentration in serum and ascitic fluid was relatively strong (r 5 0.785). Tan and Mohd (2003) used a GC/MS method to measure bisphenol A concentrations in cord blood at delivery in 180 patients at a Malaysian medical center. Bisphenol A was detected in 88% of samples. As noted in Table 9 concentrations ranged from o0.10–4.05 mg/L. Calafat et al. (2006) reported a median bisphenol A concentration of B1.4 mg/L [as estimated from a graph] in milk from 32 women. Bisphenol A was measured after enzymatic hydrolysis of conjugates. Ye et al. (2006) found measurable milk concentrations of bisphenol A in samples from 18 of 20 lactating women. Free bisphenol A was found in samples from 12 women. The median total bisphenol concentration in milk was 1.1 mg/L (range: undetectable to 7.3 mg/L). The median free bisphenol A concentration was 0.4 mg/L (range: undetectable to 6.3 mg/L). Sun et al. (2004) used an HPLC method to measure bisphenol A concentrations in milk from 23 healthy lactating Japanese women. Bisphenol A concentrations ranged from 0.28–0.97 mg/L, and the mean7SD concentration was reported at 0.6170.20 mg/L. No correlations were observed between bisphenol A and triglyceride concentrations in milk. Values from six milk samples were compared to maternal and umbilical blood samples previously reported in a study by Kuroda et al. (2003). Bisphenol A values were higher in milk, and the milk/ serum ratio was reported at 1.3. Bisphenol A values in milk were comparable to those in umbilical cord serum. [It was not clear whether milk and serum samples were obtained from the same volunteers in the two studies.] Schaefer et al. (2000) measured concentrations of bisphenol A and other compounds in uterine endometrium of women undergoing hysterectomy for uterine myoma at a German medical center. Endometrial and fat samples were obtained between 1995–1998 from 23 women (34–51 years old) with no occupational exposure. Samples were handled with plastic-free materials and stored in glass containers. Concentrations of environmental chemicals were measured in samples by GC/MS. None of 21 fat samples had detectable concentrations of Birth Defects Research (Part B) 83:157–395, 2008
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National Toxicology Program U.S. De
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NTP.will.transmit.the.NTP-CERHR.<st
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National Toxicology Program U.S. De
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nTp brief tainers.with.internal.epo
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Population Adult General. Populatio
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Table 3. Blood and Breast Milk Biom
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Figure 2b. The weight of evidence t
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in.considering.the.biological.plaus
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isphenol.A.as.efficiently.as.adult.
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isphenol.A..For.example,.this.raise
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laboRaToRy aNImal STudIeS In.contra
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of.normal.sex-based.differences.bet
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death.(168),.synaptic.plasticity.(1
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gland.carcinogen.or.that.bisphenol.
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understand.the.possible.long-term.c
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strategies.to.improve.the.sensitivi
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and.cystic.endometrial.hyperplasia.
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cutaneous. injection. 20 . vom. Saa
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are CurrenT exposures To bisphenol
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w/day;.95th.percentiles.0.289.-.0.2
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nTp ConClusions The.NTP.reached.the
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appendix a: inTerpreTaTion of blood
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Page 69 and 70: droxylase.immunoreactivity..76:423.
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Page 73 and 74: Watanabe.H,.Ohta.Y,.Iguchi.T.(2006)
Page 75 and 76: 226..vom. Saal. FS,. Cooke. PS,. Bu
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Page 101 and 102: 178 CHAPIN ET AL. Table 15 Estimate
Page 103 and 104: 180 CHAPIN ET AL. Table 17 Maximum
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Page 109 and 110: 186 CHAPIN ET AL. Secondary sources
Page 111 and 112: 188 CHAPIN ET AL. Table 25 Maternal
Page 113 and 114: 190 CHAPIN ET AL. Table 27 Bispheno
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Page 121 and 122: 198 CHAPIN ET AL. appeared to occur
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Page 125 and 126: 202 CHAPIN ET AL. suggesting that 4
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234 CHAPIN ET AL. Table 68 Toxicoki
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236 CHAPIN ET AL. treatment conditi
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238 CHAPIN ET AL. clinical signs, b
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240 CHAPIN ET AL. Table 71 Benchmar
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242 CHAPIN ET AL. group, 5 from 1 l
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244 CHAPIN ET AL. least significant
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246 CHAPIN ET AL. group was a reduc
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248 CHAPIN ET AL. 100-151 g for fem
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250 CHAPIN ET AL. 3.2.3.2 Developme
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252 CHAPIN ET AL. weights, bispheno
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254 CHAPIN ET AL. 120 mg/kg bw/day
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256 CHAPIN ET AL. comparisons condu
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258 CHAPIN ET AL. the findings of t
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260 CHAPIN ET AL. analyzed.] Anogen
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262 CHAPIN ET AL. purposeful confou
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264 CHAPIN ET AL. increased lordosi
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266 CHAPIN ET AL. that there was a
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268 CHAPIN ET AL. duration of adver
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270 CHAPIN ET AL. doses of potent e
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272 CHAPIN ET AL. Table 74 Effects
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274 CHAPIN ET AL. reproductive orga
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276 CHAPIN ET AL. tyrosine-hydroxly
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278 CHAPIN ET AL. include small sam
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280 CHAPIN ET AL. males/group. [It
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282 CHAPIN ET AL. termination, whic
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284 CHAPIN ET AL. provided a reliab
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286 CHAPIN ET AL. grooming, and out
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288 CHAPIN ET AL. method of oral do
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290 CHAPIN ET AL. reared by their d
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292 CHAPIN ET AL. has been informed
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294 CHAPIN ET AL. buffered paraform
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296 CHAPIN ET AL. unit. Further, th
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298 CHAPIN ET AL. PND 21 and housed
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300 CHAPIN ET AL. Tando et al. (200
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302 CHAPIN ET AL. Purina Certified
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304 CHAPIN ET AL. high-doses of bis
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306 CHAPIN ET AL. born to those dam
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308 CHAPIN ET AL. average weight we
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310 CHAPIN ET AL. study authors con
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312 CHAPIN ET AL. used for extracti
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314 CHAPIN ET AL. jar, and there we
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316 CHAPIN ET AL. of testes and com
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318 CHAPIN ET AL. differentiation o
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320 CHAPIN ET AL. Table 81 Summary
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322 CHAPIN ET AL. Table 82 Continue
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328 CHAPIN ET AL. 600 mg/kg bw/day)
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330 CHAPIN ET AL. (Nagao et al., 19
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332 CHAPIN ET AL. antinuclear antib
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334 CHAPIN ET AL. least 6 animals.
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336 CHAPIN ET AL. Utility (Adequacy
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338 CHAPIN ET AL. stomach weight wa
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340 CHAPIN ET AL. Schirling et al.
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342 CHAPIN ET AL. Endpoint Table 88
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344 CHAPIN ET AL. different diets b
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346 CHAPIN ET AL. with 40 mg vitami
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348 CHAPIN ET AL. the bisphenol A v
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350 CHAPIN ET AL. and determining t
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352 CHAPIN ET AL. expression [to B6
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354 CHAPIN ET AL. indicated] at 0 (
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356 CHAPIN ET AL. concentrations us
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358 CHAPIN ET AL. animals were non-
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360 CHAPIN ET AL. following adjustm
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362 CHAPIN ET AL. Table 94 Treatmen
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364 CHAPIN ET AL. Table 97 Effects
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366 CHAPIN ET AL. Table 99 Treatmen
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368 CHAPIN ET AL. Therefore the NTP
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370 CHAPIN ET AL. weeks before mati
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374 Table 101 Summary of High Utili
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376 Table 102 Summary of Limited Ut
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380 CHAPIN ET AL. from other suppli
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382 CHAPIN ET AL. U.S. populations.
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384 CHAPIN ET AL. 10. Critical desi
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386 CHAPIN ET AL. Engel SM, Levy B,
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388 CHAPIN ET AL. alpha and beta ex
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390 CHAPIN ET AL. Murray TJ, Maffin
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392 CHAPIN ET AL. Ryan BC, Vandenbe
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394 CHAPIN ET AL. Thomas P, Dong J.
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appendix iii. publiC CommenTs and p
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