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

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Table 26 Toxicokinetic Endpoints for Radioactivity in Lactating Rats Orally Administered 0.5 mg/kg bw 14 C-Bisphenol A on PND 11 a Endpoint Milk Maternal plasma Cmax, mg-eq/L 4.46 27.2 T max, hr 8 4 Elimination half-life, hr 26 31 AUC (0–48 hr), mg-eq � hr/L) 156 689 a Kurebayashi et al. (2005). Miyakoda et al. (1999) examined placental transfer of bisphenol A in rats. Wistar rats were administered an oral dose of bisphenol A (99% purity) at 10 mg/kg bw on GD 19. Blood was collected and fetuses were removed at 1, 3, and 24 hr following dosing. Bisphenol A concentrations were measured in plasma and fetuses by GC/MS. [A statement in Figure 3 of the study indicated that values were the means of 5 or 7 experiments; it is possible the authors meant that 5 or 7 dams were dosed.] Concentrations of bisphenol A peaked in maternal plasma and fetuses within 1 hr of dosing, with bisphenol A concentrations measured at B34 ppb [lg/L] in maternal plasma and 11 ppb [lg/kg] in fetuses. At 3 hr after dosing, bisphenol A concentrations were B10% of peak concentrations in maternal plasma and 40% of peak concentrations in fetuses. At 24 hr post-dosing, bisphenol A concentrations in fetuses were detected at 70% of peak value and concentrations in fetuses were more than twice the concentrations in maternal plasma. Study authors concluded that bisphenol A is rapidly transferred to the fetus and tends to remain longer in fetuses than in maternal blood. Snyder et al. (2000) examined the toxicokinetics of bisphenol A in lactating rats. On PND 14, lactating CD rats were gavaged with 100 mg/kg bw 14 C-bisphenol A. Milk, blood, and organs were collected from 2–4 dams/ group at 1, 8, 24, or 26 hr after dosing. [While the text indicates collection of samples at 26 hr, Table 3 of the study indicates collection at 24 hr. The collection time reported in the study table was used when there were discrepancies between text and table.] Animals were injected with oxytocin before milk collection. Radioactivity in pup carcasses was measured at 2, 4, 6, and 24 hr following exposure of dams; 8–16 pups/time period were examined [pup data does not appear to be analyzed by litter]. Samples were analyzed by scintillation counting, HPLC, and/or nuclear magnetic resonance. At 1 and 8 hr following exposure, the highest percentage of the radioactive dose was detected in intestine with contents (75–83%). Among the other organs examined, the highest percentage of the radioactive dose was detected in liver (0.38–0.74%) and much lower percentages were detected in kidney and lung (r0.02%). Low percentages of the radioactive dose were also detected in milk (r0.0020%), blood (B0.006%), plasma (B0.01%), and fat (r0.004%). Compared to earlier time periods, radioactivity levels were lower at 24 hr post-dosing (26% of the dose detected in intestine and contents), but distribution was similar. At all 3 sampling time points, radioactivity levels were highest in plasma 4 blood 4 milk. The major radioactivity peak in Birth Defects Research (Part B) 83:157–395, 2008 BISPHENOL A 189 plasma was represented by bisphenol A glucuronide at 1, 8, and 26 hr following exposure. Bisphenol A glucuronide also represented the major radioactive peak detected in milk. Radioactivity levels in pups amounted to o0.01% of the maternal dose. Radioactivity levels in pups tended to increase over time. From 2–24 hr following exposure, mean7SD radioactivity levels rose from 44724 to 78711 mg bisphenol A eq/pup. Yoshida et al. (2004) compared bisphenol A concentrations in rats and their offspring during the lactation period. The main focus of the study was developmental toxicity, which is discussed in Section 3.2.3.2. In the distribution study, Donryu rats (12–19/group) were gavaged with bisphenol A at 0 (carboxymethylcellulose solution), 0.006, or 6 mg/kg bw/day from GD 2 to the day before weaning (21 days post-delivery). Bisphenol A concentrations were measured in maternal and pup serum, milk, and pup liver by GC/MS on PND 10, 14, and/or 21. Milk samples were obtained from pup stomachs. Pup serum and liver samples were pooled. Two to six dams/litter were examined in each dose group and time period. Samples of tap water, drinking water from plastic containers, and feed were measured for bisphenol A content by HPLC. Bisphenol A was not detected in fresh tap water but was detected at B3 mg/L following storage of that water in plastic containers. Bisphenol A concentration in feed was B40 mg/kg. Results for maternal and fetal tissues are summarized in Table 27. Bisphenol A concentrations in the serum of high-dose-dams were significantly elevated compared to the control group on PND 21. No other significant differences were observed in bisphenol A concentrations in samples between treated and control groups. Kim and Huang (2003) used an HPLC method to measure bisphenol A concentrations in rat dams and their offspring. Dams were gavaged with bisphenol A (499.7% purity) at doses of 0 (corn oil vehicle), 0.002, 0.020, 0.200, 2, or 20 mg/kg bw/day on GD 7–17. Dams and offspring were killed at 21 days following parturition, and serum was collected for measurement of bisphenol A. Development effects observed in this study are summarized in Section 3.2.1.1. Bisphenol A was not detected in the serum of dams at the two lowest doses. Respective concentrations of bisphenol A in the serum of dams at the 3 highest doses were 0.900, 0.987, and 1.00 mg/L. In offspring, bisphenol A was not detected in serum at the 3 lowest doses. At the 2 highest doses, the respective concentrations of bisphenol A in offspring were 0.69 and 0.74 mg/L in males and 0.71 and 0.82 mg/ L in females. Shin et al. (2002) examined elimination of bisphenol A from maternal–fetal compartments of rats. On 1 day between GD 17 and 19, four Sprague–Dawley rats were i.v. injected with 2 mg/kg bw bisphenol A. Amniotic fluid, placenta, and fetuses were collected at multiple intervals between 5 min and 8 hr following injection. Bisphenol A concentrations in samples were measured by HPLC. Transfer rate constants and clearance rates were determined using a five-compartment model consisting of maternal central, maternal tissue, placental, fetal, and amniotic fluid compartments. Toxicokinetic findings are summarized in Moors et al. (2006) evaluated the kinetics of bisphenol A in pregnant rats on GD 18 after a single i.v. dose of 10 mg/kg bw. Unconjugated bisphenol A represented almost 80% of total bisphenol A
190 CHAPIN ET AL. Table 27 Bisphenol A Concentrations in Maternal and Pup Samples During Lactation in Rats Gavaged With Bisphenol A a Dose group, mg/kg bw/day 0 0.006 6 Sample Time of analysis Sex Bisphenol A concentration, ppb [mg/L or mg/kg] Dam b Serum PND 21 370 470 1174 Milk PND 10 2879 8721 873 PND 14 255778 20577 185750 Pup c Serum PND 10 Female 4 10 23 Male 15 5 7 PND 14 Female 5 4 3 Male 4 5 4 PND 21 Female 9 3 9 Male 14 9 20 Liver PND 10 Female 13 12 17 Male 9 9 14 Pup c Liver PND 14 Female 22 100 18 Male 45 14 16 PND 21 Female 60 70 37 Male 69 9 60 a Yoshida et al. (2004). b Values are presented as mean7SD. c Pup samples were pooled. Endpoint Table 28 Toxicokinetic Endpoints for Bisphenol A in Pregnant Rats iv Dosed With 2 mg/kg bw Bisphenol A a AUC, mg � hr/L Elimination half-life, hr Mean residence time, hr Cmax, mg/L Tmax, hr Values presented as mean7SD. a Shin et al. (2002). Compartment Maternal serum Placenta Fetus Amniotic fluid 905.57275.8 2.570.9 3.071.1 927.37194.3 No data 40097962.7 2.270.8 2.070.5 1399.27323.7 0.170.1 1964.77678.5 2.270.8 3.070.9 7947360.6 0.670.3 180.47102.0 3.973.1 5.674.7 75.1759.7 0.370.2 Table 29 Intercompartmental Transfer and Clearances in Pregnant Rats Following Intravenous Bisphenol A a Compartment Transfer rate constant, hr -1 Maternal central to maternal tissue Maternal tissue to maternal central Maternal central to placental Placental to maternal central Placental to fetal Fetal to placental Fetal to amniotic fluid Fetal Amniotic fluid to fetal Amniotic fluid to placental Placental to amniotic fluid Maternal central Values presented as mean7SD. a Shin et al. (2002). 3.472.6 1.771.3 0.770.5 23.6714.7 46.4729.2 22.8728.0 0.0000170.00002 0.006270.0044 14.0721.0 7.976.7 1.071.3 0.970.6 Clearance rate mL/min 38.2726.5 50.2736.7 8.375.4 2.271.3 4.172.1 7.676.0 0.0000170.00001 0.002470.0015 0.871.1 0.770.7 0.170.1 9.775.3 Birth Defects Research (Part B) 83:157–395, 2008
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National Toxicology Program U.S. De
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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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appendix a: inTerpreTaTion of blood
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µg/kg.bw/day.based.on.the.assumpti
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concentrations.from.maternal,.fetal
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12.. Padmanabhan. V,. Siefert. K,.
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Page 103 and 104: 180 CHAPIN ET AL. Table 17 Maximum
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Page 107 and 108: 184 CHAPIN ET AL. fetuses (3.572.7
Page 109 and 110: 186 CHAPIN ET AL. Secondary sources
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Page 141 and 142: 218 Model and exposure Husbandry a
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Page 147 and 148: 224 Table 57 In Vitro Genetic Toxic
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Page 151 and 152: 228 CHAPIN ET AL. Table 59 Developm
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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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