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

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BISPHENOL A Table 42 Toxicokinetic Endpoints for Bisphenol A by LC-MS/MS in Rats, Monkeys, and Chimpanzees a 10 mg/kg bw 100 mg/kg bw Endpoints Oral S.C. Oral S.C. Rat (data presented as mean7SD) Cmax, mg/L 2.171.6 746780 47.5710.6 26317439 Tmax, hr 0.770.3 0.870.3 0.570.0 1.270.8 t1/2, hr not calculated 3.270.7 not calculated 4.570.7 AUC0–4 h, mg � hr/L 4.2 b 15427200 43.279.7 692671071 AUC0–24 h, mg � hr/L 7.2 b Monkey (data presented as mean7SD) 19777182 3507294 15,57672263 Cmax, mg/L 11.572.2 421373319 28.673.9 701073045 Tmax, hr 1.070.9 1.770.6 3.371.2 2.771.2 t1/2, hr 8.973.0 3.870.8 4.570.7 12.973.6 AUC0–4 h, mg � hr/L 21.476.1 882874309 85.3718.6 19,98177567 AUC0–24 h, mg � hr/L Chimpanzee (data presented as mean for 2 animals) 42.577.3 18,85573870 350713 79,796721,750 Cmax, mg/L 5.5 703 Dose not administered Tmax, hr 0.8 1.0 t1/2, hr 6.8 4.2 AUC0–4 h, mg � hr/L 13.3 2148 AUC0–24 h, mg � hr/L 33.1 6000 a Tominaga et al. (2006). b 1 or 2 animals. was lowest in ratsochimpanzeesomonkeys following exposure through either route. In most cases, bisphenol A was not detected in rat serum following oral administration of the 10 mg/kg bw dose. In all species, higher bioavailability was observed with s.c. than oral dosing. In a subsequent report (Tominaga et al., 2006), these authors noted that ELISA may overestimate bisphenol A concentrations due to non-specific binding. They reported measurements by LC-MS/MS in animals evaluated using the same study design [possibly the same specimens reported previously]. These results are summarized in Table 42. The authors proposed that primates, including humans, may completely glucuronidate orally-administered bisphenol A on its first pass through the liver and excrete it in the urine whereas bisphenol A remains in the rat for a more extended period due to enterohepatic recirculation. They suggested that the rat may not be a good model for human bisphenol A kinetics. 2.1.2.3 Metabolism: Information is arranged in this section according to species. In rats, study summaries are arranged in order of those providing general or routespecific information on metabolites, specifics on organs or enzyme isoforms involved in metabolism, and pregnancy-, sex-, or age-related effects on metabolism. Pottenger et al. (2000) examined the effects of dose and route on toxicokinetics of bisphenol A in rats. Disposition of bisphenol A and its metabolites in urine and feces is described in this section, while results of the toxicokinetics study are described in Section 2.1.2.2. Five adult F344 rats/sex/group were dosed with 14 C-bisphenol A (99.3% radiochemical purity)/non-radiolabeled bisphenol A (99.7% purity) at doses of 10 or 100 mg/kg bw by oral gavage or i.p. or s.c. injection. Excreta were collected for 7 days. Samples were analyzed by HPLC or HPLC/ electrospray ionization/MS. The percentage of radioactivity recovered from all groups was 84–98%. Fecal elimination represented the largest percentage of Birth Defects Research (Part B) 83:157–395, 2008 199 radioactivity in all exposure groups (52–83%). Eight peaks were identified in feces, and the largest peak (representing 86–93% of radioactivity) was for unchanged bisphenol A. Elimination of radioactivity through urine was B2-fold higher in females (21–34%) than males (13–16%) in all dose groups. Fourteen different peaks were identified in urine. It was estimated that radioactivity in urine was represented by bisphenol A monoglucuronide (57–87%), bisphenol A (3–12%), and bisphenol A sulfate (2–7%). Some differences were noted for retention of radioactivity following dosing by gavage (0.03–0.26%), i.p. injection (0.65–0.85%), and s.c. injection (1.03–1.29%). Metabolites associated with bisphenol A exposure were examined in a second study by Pottenger et al. (2000). Three rats/sex/dose/route/time point were dosed with 14 C-bisphenol A/non-radiolabeled bisphenol A at 10 or 100 mg/kg bw by oral gavage or i.p. or s.c. injection. Rats were killed at 2 different time points following dosing, Tmax, and the time when bisphenol A concentrations were no longer quantifiable. Times at which rats were killed were determined by data obtained during the first study. Plasma samples were pooled at each time period and examined by HPLC or HPLC/ electrospray ionization/MS. Qualitative and quantitative differences were observed for parent compound and metabolites in plasma following exposure through different routes. Following oral exposure, bisphenol A glucuronide was the most abundant compound detected in plasma at both time periods (Cmax and time when parent compound was not quantifiable) and represented 68–100% of total radioactivity. Following i.p. or s.c. exposure, unmetabolized bisphenol A was the most abundant compound at Tmax; levels of radioactivity represented by unmetabolized bisphenol A were 27– 51% following i.p. exposure and 65–76% following s.c. exposure. Only 2–8% of radioactivity was represented by bisphenol A following oral exposure. Some compounds observed following i.p. or s.c. exposure were not
200 CHAPIN ET AL. Table 43 Biliary Excretion in Male and Female Rats Exposed to 0.1 mg/kg bw 14 C-Bisphenol A Through the Oral or Intravenous Route a Male Female Parameters I.V. Oral I.V. Oral Biliary excretion, % 0–2 hr 0–4 hr 0–6 hr Radioactivity in bile represented by glucuronide, % Dose excreted as glucuronide in bile, % a Kurebayashi et al. (2003). 48 61 66 84 55 32 44 50 86 43 35 50 58 87 50 28 39 45 88 observed following oral exposure. A compound tentatively identified as a sulfate conjugate was observed following i.p. exposure and represented a small portion of radioactivity. An unresolved peak of 3 compounds was observed following i.p. or s.c. exposure, at the time when parent compound was not quantifiable and represented that major percent of radioactivity for that time point. Three additional unidentified, minor peaks were observed following i.p. or s.c. but not oral exposure. The major sex differences observed were higher Cmax values for bisphenol A and bisphenol A glucuronide in females than males, especially following i.p. administration. A review by the European Union (2003) noted that the substantially higher concentrations of parent compound with i.p. and s.c. compared to oral exposure indicated the occurrence of first-pass metabolism following oral intake. Elsby et al. (2001) examined bisphenol A metabolism by rat hepatocytes. In the hepatocyte metabolism study, hepatocytes were isolated from livers of adult female Wistar rats and incubated in dimethyl sulfoxide (DMSO) vehicle or bisphenol A 100 or 500 mM [23 or 114 mg/L] for 2 hr. Metabolites were identified by HPLC or LC/MS. Data were obtained from 4 experiments conducted in duplicate. At both concentrations, the major metabolite was identified as bisphenol A glucuronide, which was the only metabolite identified following incubation with 100 mM bisphenol A. Two additional minor metabolites identified at the 500 mM concentration included 5-hydroxy-bisphenol A-sulfate and bisphenol A sulfate. Another part of the study comparing metabolism of bisphenol A by rat and human metabolites is discussed in Section 2.1.1.3. Another study (Pritchett et al., 2002) comparing metabolism of bisphenol A in humans, rats, and mice is also summarized in Section 2.1.1.3. In neonatal rats gavaged with 1 or 10 mg/kg bw 14 C-bisphenol A on PND 4, 7, and 21 and adult rats gavaged with 10 mg/kg bw bisphenol A, the major compounds detected in plasma were bisphenol A glucuronide and bisphenol A (Domoradzki et al., 2004). Up to 13 radioactive peaks were identified in neonatal rats dosed with 10 mg/kg bw and 2 were identified in neonates dosed with 1 mg/kg bw/day. At the 10 mg/kg bw dose, the concentration of bisphenol A glucuronide detected in plasma increased with age. Metabolic profiles were generally similar in males and 40 females. The study authors noted that metabolism of bisphenol A to its glucuronide conjugate occurs as early as PND 4 in rats. However, age-dependent differences were observed in neonatal rats, as noted by a larger fraction of the lower dose being metabolized to the glucuronide. More details from this study are included in Section 2.1.2.2. Kurebayashi et al. (2005) used a thin layer chromatography technique to examine metabolite profiles in blood, urine, and feces of 3 male rats orally dosed with 0.5 mg/kg bw 14 C-bisphenol A. [The procedure did not identify metabolites.] Parent bisphenol A represented B2% of the dose in plasma at 0.25 and 6 hr post-dosing and B0.3% of the dose at 24 hr after exposure. Unmetabolized bisphenol A represented 1.6% of compounds in urine and 77.2% of compounds in feces collected over a 24-hr period. Free bisphenol A represented 47.1% of compounds in urine following bglucuronidase hydrolysis of urine, and there was an almost equivalent decrease in a metabolite the study authors identified as ‘‘M2.’’ Therefore, the study authors stated that M2 was most likely bisphenol A glucuronide. M2 was the major metabolite identified in plasma (B74– 77%) and urine (B40%). The European Union (2003) reviewed studies by Atkinson and Roy ([1995a,b) that reported two major and several minor adducts in DNA obtained from the liver of CD-1 rats dosed orally or i.p. with 200 mg/kg bw bisphenol A. Chromatographic mobility of the two major adducts was the same as that observed when bisphenol A was incubated with purified DNA and a peroxidase or microsomal P450 activation system. The profile closely matched that of adducts formed with the interaction between bisphenol Oquinone and purified rat DNA deoxyguanosine 3 0 -monophosphate. Formation of the adduct appeared to be inhibited by known inhibiters of cytochrome P (CYP) 450. It was concluded that bisphenol A is possibly metabolized to bisphenol O-quinone by CYP450. Biliary excretion of bisphenol A and its metabolites following oral or i.v. dosing with bisphenol A was examined by Kurebayashi et al. (2003). Bile ducts of 3 rats/sex/group were cannulated, and the rats were dosed with 0.1 mg/kg bw 14 C-bisphenol A (499% radiochemical purity) in phosphate buffer vehicle by oral gavage or i.v. injection. Biliary fluid was collected every 2 hr over a 6-hr period to determine percent total biliary excretion and percent of dose represented by bisphenol A glucuronide. Results are summarized in Table 43. The study authors noted that the importance of biliary excretion following oral or i.v. dosing. 14 Cbisphenol A-glucuronide was the predominant metabolite in bile. In another study by Kurebayashi et al. (2003), biliary, fecal, and urinary metabolites were examined in male rats gavaged with 100 mg/kg bw bisphenol A or D16bisphenol A in corn oil. Bile was collected over an 18-hr period, and urine and feces were collected over a 72-hr period. The primary metabolite detected in urine was bisphenol A glucuronide, which represented 6.5% of the dose. Lower percentages of the dose (r1.1%) were present in urine as bisphenol A and bisphenol A sulfate. In feces, the primary compound detected was bisphenol A, which represented 61% of the dose. No glucuronide or sulfate conjugated metabolites of bisphenol A were detected in feces. Most of the dose in bile consisted of Birth Defects Research (Part B) 83:157–395, 2008
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National Toxicology Program U.S. De
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National Toxicology Program U.S. De
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Population Adult General. Populatio
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Page 81 and 82: 158 CHAPIN ET AL. the CERHR Core Co
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Page 85 and 86: 162 CHAPIN ET AL. concentrations in
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Page 89 and 90: 166 CHAPIN ET AL. Table 6 Continued
Page 91 and 92: 168 CHAPIN ET AL. comparison of the
Page 93 and 94: 170 CHAPIN ET AL. Table 8 Urinary C
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Page 97 and 98: 174 CHAPIN ET AL. Table 11 Bispheno
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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
Page 105 and 106: 182 CHAPIN ET AL. 2.0 GENERAL TOXIC
Page 107 and 108: 184 CHAPIN ET AL. fetuses (3.572.7
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
Page 115 and 116: 192 CHAPIN ET AL. Table 31 Qualitat
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Page 127 and 128: 204 CHAPIN ET AL. low following ora
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Page 133 and 134: 210 CHAPIN ET AL. related. No histo
Page 135 and 136: 212 CHAPIN ET AL. Table 52 Continue
Page 137 and 138: 214 CHAPIN ET AL. Model and exposur
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Page 141 and 142: 218 Model and exposure Husbandry a
Page 143 and 144: 220 CHAPIN ET AL. Table 54 Differen
Page 145 and 146: 222 CHAPIN ET AL. Table 56 Anti-And
Page 147 and 148: 224 Table 57 In Vitro Genetic Toxic
Page 149 and 150: 226 CHAPIN ET AL. Table 58 In Vivo
Page 151 and 152: 228 CHAPIN ET AL. Table 59 Developm
Page 155 and 156: 232 CHAPIN ET AL. Table 64 Tissue R
Page 159 and 160: 236 CHAPIN ET AL. treatment conditi
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Page 163 and 164: 240 CHAPIN ET AL. Table 71 Benchmar
Page 165 and 166: 242 CHAPIN ET AL. group, 5 from 1 l
Page 167 and 168: 244 CHAPIN ET AL. least significant
Page 169 and 170: 246 CHAPIN ET AL. group was a reduc
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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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