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

More documents

Recommendations

Info

Results were reported to be similar for the 2 species, and unless otherwise indicated, data were shown for S. purpuratus. In additional studies, sea urchin embryos were incubated in bisphenol A at 0–500 mg/L with and without addition of tamoxifen or bisphenol A at 0– 750 mg/L with and without the addition of ICI 182,780. Data were analyzed by ANOVA followed by Tukey– Kramer test or Tukey or Student-Newman–Keuls tests for pair-wise multiple comparison. An EC 50 of 226.6 mg/ L (lower limit: 121.6, upper limit: 323.5 mg/L) was estimated for developmental toxicity associated with bisphenol A exposure. Based on EC50 values, 17bestradiol was B15 times more potent than bisphenol A. Tamoxifen inhibited developmental toxicity, and ICI 182,780 enhanced the developmental toxicity induced by bisphenol A; similar results were obtained for 17bestradiol. The study authors concluded that bisphenol A induced developmental toxicity in sea urchins through a tamoxifen-sensitive mechanism at levels exceeding environmentally relevant concentrations. Strengths/Weaknesses: The use of 2 species and multiple concentrations are strengths. Utility (Adequacy) for CERHR Evaluation Process: This study may have utility for environmental assessment, but is not useful for human risk assessment. Andersen et al. (1999b), supported by the Danish Strategic Environmental Research Program, evaluated the effects of bisphenol A on female sexual maturation in the zoo planktonic crustacean Acartia tonsa. Eggs were grown in the presence of the algal food source for the organism after exposure of the algae to bisphenol A (499% purity) for 3 hr to promote sorption by the algae of the test chemical [culture ware not discussed]. The treated algae were added to Acartia tonsa eggs to give nominal bisphenol A concentrations of 0.2, 2, and 20 mg/ L. [Actual concentrations were not reported. An untreated or vehicle-treated control appears to have been used.] 17b-Estradiol 23 mg/L was used as a positive control, and 2,3-dichlorophenol 13.6 mg/L was used as a negative control. On Day 8 of incubation, 10–25 juvenile Acartia tonsa/group were transformed to an egg-collection apparatus, in which exposure to treated algae continued. Eggs were collected daily and counted until Day 12, at which time a stable adult level of egg production was established. Egg production by group was compared using Student t-test. [A repeated-measures test appears not to have been used.] A significant increase in egg production was shown on Day 10 in animals treated with bisphenol A 20 mg/L and 17bestradiol 23 mg/L compared to control. The authors concluded that bisphenol A accelerated female reproductive maturation in Acartia tonsa and that the effect appeared to be estrogenic. Strengths/Weaknesses: Strengths are the use of multiple exposure levels, the inventive method of feeding bisphenol A to the test organisms, and the use of 17bestradiol as a positive control. Utility (Adequacy) for CERHR Evaluation Process: This study may have utility for environmental assessment, but is not useful for human risk assessment. Watts et al. (2001), supported by the European Union, examined development and reproduction in 2 generations of non-biting midges (Chironomus riparius) exposed to bisphenol A. The study began with incubation of 4 egg ropes/group in media containing vehicle, bisphenol A, Birth Defects Research (Part B) 83:157–395, 2008 BISPHENOL A 309 or ethinyl estradiol [apparently at the same concentrations described below]. Twenty first-instar larvae from the appropriate media were added to each exposure glass jar containing dechlorinated water and sediment spiked with bisphenol A [purity not indicated] at concentrations of 0 (ethanol vehicle control and dechlorinated tap water control), o0.010, 0.078, 0.55, 77, 750, or 10,400 mg/L. Four replicate jars were prepared for each dose level. Concentrations in sediment were verified. Numbers and sexes of adults emerging from each replicate jar were determined. Egg ropes produced by the first generation were counted and placed in media containing test solutions or vehicle controls. Four egg ropes/group were selected and used to reseed the sediments with the second generation of larvae. Adults emerging from the second generation were counted. Statistical significance was determined by ANOVA. In the first generation, adult emergence was delayed in females from the o0.010, 0.55, and 77 mg/L bisphenol A groups but was not affected in males. Males were reported to emerge significantly earlier than females. In the second generation, emergence of males and female adults was significantly delayed at Z0.078 mg/L bisphenol A. At concentrations of 0.010– 750 mg/L, there were no significant differences in the percentage of adults emerging in either generation. No second-generation adults emerged in the group exposed to 10,400 mg/L. There were no effects on sex ratio. Exposure to bisphenol A did not significantly affect the number of eggs produced by the first generation. In contrast to bisphenol A, exposure to ethinyl estradiol accelerated adult emergence. The study authors concluded that the endpoints evaluated indicated general sediment toxicity but were not useful for detecting estrogenic effects. Strengths/Weaknesses: The wide range of exposure levels and the use of ethinyl estradiol as a positive control are strengths. Utility (Adequacy) for CERHR Evaluation Process: This study may have utility for environmental assessment, but is not useful for human risk assessment. Watts et al. (2003), supported by the European Union, examined the effects of bisphenol A exposure on moulting and mouthpart deformities in non-biting midge (Chironomus riparius) larvae. Four egg-ropes/ group were incubated in glass jars in media containing bisphenol A [purity not indicated] at 0 (ethanol vehicle or dechlorinated water group), 0.010, 0.1, 1, 10, 100, or 1000 mg/L. Concentrations of bisphenol A were verified in the 1000 mg/L group. On hatching, exposures were continued in 10 larvae/group. Endpoints examined included survival, time of moulting to successive instars, wet weight 2 days after moulting to fourth instar, and mouthpart morphology in fourthinstar head capsules. Statistical analyses included ANO VA, Tukey–Kramer multiple comparison test, and Kruskal–Wallis test. [Effects were similar in ethanol and water controls.] Moulting was delayed and larval weights were significantly decreased in the 1000 mg/L bisphenol A group. Deformities of the mentum were significantly increased in the range of 0.010–1 mg/L bisphenol A. The effects of ethinyl estradiol were also examined, and the study authors noted similar patterns of malformations, with greater incidence following exposure to ethinyl estradiol than bisphenol A. The
310 CHAPIN ET AL. study authors concluded that exposure to bisphenol A delayed moulting and increased mouth part deformities at concentrations that were at opposite ends of the exposure range. Strengths/Weaknesses: This study is similar in its strengths to that of Watts et al. (2001). Utility (Adequacy) for CERHR Evaluation Process: This study may have utility for environmental assessment, but is not useful for human risk assessment. 3.2.10.2 Frog: Iwamuro et al. (2003), support not indicated, conducted a series of studies to examine the effects of bisphenol A exposure on development of the frog Xenopus laevis. In a study to assess survival and morphological abnormalities, 60–100 Stage 7 embryos/ group were exposed to bisphenol A [purity not indicated] at 0 (ethanol vehicle), 10, 20, 25, 30, 50, or 100 mM [0, 2.3, 4.6, 5.7, 6.8, 11, or 23 mg/L; culture ware not discussed]. Siblings were randomly distributed among different treatment groups. Survival was assessed at 48, 96, and 120 hr. At least 3 embryos/group were examined for malformations at 5–7 days following fertilization. Data were analyzed by w 2 test. Survival of embryos was significantly reduced following exposure to Z25 mM [5.7 mg/L] bisphenol A for 96 or 120 hr. Complete mortality was observed at concentrations Z50 mM [11 mg/L]. The study authors calculated a median LD 50 for survival of 21 mM [4.8 mg/L]. The malformation rate was reported for the 10 and 25 mM [2.3 and 4.6 mg/L] group, and significant increases in malformations occurred in the 25 mM [4.6 mg/L] group. The types of malformations were reported as scoliosis, swollen head, and shortened distance between eyes. The effects of 17b-estradiol were also examined. An increase in malformations was observed with exposure to 10 mM 17b-estradiol, but there was no effect on survival. In a second study, metamorphosis was observed in 10– 12 tadpoles (Stage 52) placed in solutions containing 10 or 25 mM [2.3 or 5.7 mg/L] bisphenol A [purity not indicated] with and without the addition of 0.1 mM thyroxin for 21 days. Expression of thyroid hormone receptor-b gene was measured by RT-PCR in three regions (head, trunk, and tail) of tadpoles that were exposed to 10 or 100 mM [2.3 or 23 mg/L] bisphenol A with and without the addition of 0.1 mM triiodothyronine or thyroxin. Negative controls were exposed to ethanol/ DMSO vehicle. Metamorphosis data were analyzed by Duncan new multiple range test. Bisphenol A inhibited significantly both spontaneous and thyroxine-induced metamorphosis. All concentrations of bisphenol A reduced expression of thyroid hormone receptor-b hormone and inhibited increases in thyroxine- and triiodothyronine-induced expression. In a third study, tails were removed from 4 tadpoles/ group and cultured for 4 days in media containing 10 or 100 mM [2.3 or 23 mg/L] bisphenol A with and without the addition of 0.1 mM triiodothyronine. Negative controls were exposed to ethanol/DMSO vehicles. Data were analyzed by Duncan new multiple range test. Growth of the tails was measured over a 4-day period. Neither bisphenol A dose significantly affected tail growth. Both bisphenol A doses blocked tail shortening that was induced by triiodothyronine . The study authors concluded that high-doses of bisphenol A adversely affect development of Xenopus laevis embryos and larvae. Strengths/Weaknesses: The wide range of exposure levels is a strength. Utility (Adequacy) for CERHR Evaluation Process: This study may have utility for environmental assessment, but is not useful for human risk assessment. Oka et al. (2003), support not indicated, examined the effects of bisphenol A exposure on development of the frog Xenopus laevis. Embryos were exposed to the ethanol vehicle or 10–100 mM [2.3–23 mg/L] bisphenol A from developmental stage 6 until the early tadpole stage (late stage 10) [purity not indicated, and culture ware not discussed]. Embryos were harvested at Stages 19, 23, 33/ 34, and 40 and prepared for histological examination to determine the presence of apoptotic cells. Apoptosis was also assessed using a TUNEL staining method. Ten embryos were killed at the tail bud stage (Stage 35/36, 37/38, and 40), and genomic DNA was isolated and examined by electrophoreses to determine if 180 base pair ladders indicative of apoptosis were present. [No information was provided on the number of individual doses examined or the number of embryos exposed/ dose. No quantitative data were presented by authors, and it does not appear that data were statistically analyzed.] Embryos exposed to 40–100 mM [9.1–23 mg/L] bisphenol A died during the gastrula stage. Developmental abnormalities were observed in embryos exposed to 20 mM [4.6 mg/L] bisphenol A. The abnormalities included open neural tubes at Stage 19, morphological defects at Stages 23 and 33/34, and crooked vertebrate, swollen abdomen, and malformed head at Stage 40. Malformations persisted following Stage 40, and death occurred during the tadpole stage. In Stage 33/34 and 40 embryos of the 20 mM [4.6 mg/L] group, apoptotic cells were observed in the prosencephalon, mesencephalon, rhombencephalon, and spinal cord. Apoptosis was confirmed using the TUNEL staining method. Using the DNA ladder method, it was found that apoptosis also occurred at Stages 35/36, 37/38, and 40. The authors briefly stated that they tested Stage 10, 19, or 23 embryos and found normal development following bisphenol A exposure. [No additional details were provided.] The effects of 17b-estradiol were also examined. Malformations were observed in embryos exposed to 10 mM 17b-estradiol, but apoptotic cells were not observed in the nervous system. A very brief description was provided of a study in which embryos were exposed simultaneously to 20 mM [4.6 mg/L] bisphenol A and 1–10 mM 17b-estradiol. Co-exposure with 17b-estradiol did not inhibit bisphenol A-induced apoptosis. The study authors concluded that bisphenol A induced malformations and apoptosis in Xenopus laevis at concentrations exceeding environmental levels and that the effects did not appear to occur through an estrogenic mechanism. Strengths/Weaknesses: The use of 17b-estradiol exposure to suggest a non-estrogenic mechanism of bisphenol A toxicity is a strength. The omission of some important details and the high concentrations are weaknesses. Utility (Adequacy) for CERHR Evaluation Process: This study may have utility for environmental assessment, but is not useful for human risk assessment. Sone et al. (2004), supported by the Japanese Ministry of Environment and Ministry of Education, Culture, Sports, Science, and Technology, examined the effects of Birth Defects Research (Part B) 83:157–395, 2008
Page 1:
National Toxicology Program U.S. De
Page 4 and 5:
[This page inTenTionally lefT blank
Page 6 and 7:
Page 8 and 9:
NTP.will.transmit.the.NTP-CERHR.<st
Page 10:
National Toxicology Program U.S. De
Page 13 and 14:
Page 15 and 16:
nTp brief tainers.with.internal.epo
Page 17 and 18:
Population Adult General. Populatio
Page 19 and 20:
Table 3. Blood and Breast Milk Biom
Page 21 and 22:
Figure 2b. The weight of evidence t
Page 23 and 24:
in.considering.the.biological.plaus
Page 25 and 26:
isphenol.A.as.efficiently.as.adult.
Page 27 and 28:
isphenol.A..For.example,.this.raise
Page 29 and 30:
laboRaToRy aNImal STudIeS In.contra
Page 31 and 32:
of.normal.sex-based.differences.bet
Page 33 and 34:
death.(168),.synaptic.plasticity.(1
Page 35 and 36:
gland.carcinogen.or.that.bisphenol.
Page 37 and 38:
understand.the.possible.long-term.c
Page 39 and 40:
strategies.to.improve.the.sensitivi
Page 41 and 42:
• • Howdeshell.et.al. (55).repo
Page 43 and 44:
and.cystic.endometrial.hyperplasia.
Page 45 and 46:
cutaneous. injection. 20 . vom. Saa
Page 47 and 48:
are CurrenT exposures To bisphenol
Page 49 and 50:
w/day;.95th.percentiles.0.289.-.0.2
Page 51 and 52:
nTp ConClusions The.NTP.reached.the
Page 53 and 54:
appendix a: inTerpreTaTion of blood
Page 55 and 56:
µg/kg.bw/day.based.on.the.assumpti
Page 57 and 58:
concentrations.from.maternal,.fetal
Page 59 and 60:
12.. Padmanabhan. V,. Siefert. K,.
Page 61 and 62:
In..Research.Triangle.Park,.NC:.RTI
Page 63 and 64:
65.. Alonso-Magdalena. P,. Laribi.
Page 65 and 66:
91.. Calabrese.EJ,.Baldwin.LA.(2003
Page 67 and 68:
Thyroid.Function.in.Juvenile.Female
Page 69 and 70:
droxylase.immunoreactivity..76:423.
Page 71 and 72:
stanceschimiques.gc.ca/challenge-de
Page 73 and 74:
Watanabe.H,.Ohta.Y,.Iguchi.T.(2006)
Page 75 and 76:
226..vom. Saal. FS,. Cooke. PS,. Bu
Page 77 and 78:
solid.phase.extraction-high.perform
Page 79 and 80:
appendix i. nTp-Cerhr bisphenol a e
Page 81 and 82:
158 CHAPIN ET AL. the CERHR Core Co
Page 83 and 84:
160 CHAPIN ET AL. referred to as 4,
Page 85 and 86:
162 CHAPIN ET AL. concentrations in
Page 87 and 88:
164 CHAPIN ET AL. Food (no. sampled
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
Page 95 and 96:
172 CHAPIN ET AL. the blood of male
Page 97 and 98:
174 CHAPIN ET AL. Table 11 Bispheno
Page 99 and 100:
176 CHAPIN ET AL. Table 13 Summarie
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
Page 117 and 118:
194 CHAPIN ET AL. Table 33 Toxicoki
Page 119 and 120:
Page 121 and 122:
198 CHAPIN ET AL. appeared to occur
Page 123 and 124:
200 CHAPIN ET AL. Table 43 Biliary
Page 125 and 126:
202 CHAPIN ET AL. suggesting that 4
Page 127 and 128:
204 CHAPIN ET AL. low following ora
Page 129 and 130:
206 CHAPIN ET AL. scaling and speci
Page 131 and 132:
208 CHAPIN ET AL. 60-100% in each d
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
Page 139 and 140:
216 CHAPIN ET AL. Model and exposur
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 153 and 154:
Page 155 and 156:
232 CHAPIN ET AL. Table 64 Tissue R
Page 157 and 158:
Page 159 and 160:
236 CHAPIN ET AL. treatment conditi
Page 161 and 162:
238 CHAPIN ET AL. clinical signs, b
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
Page 171 and 172:
248 CHAPIN ET AL. 100-151 g for fem
Page 173 and 174:
250 CHAPIN ET AL. 3.2.3.2 Developme
Page 175 and 176:
252 CHAPIN ET AL. weights, bispheno
Page 177 and 178:
254 CHAPIN ET AL. 120 mg/kg bw/day
Page 179 and 180:
256 CHAPIN ET AL. comparisons condu
Page 181 and 182: 258 CHAPIN ET AL. the findings of t
Page 183 and 184: 260 CHAPIN ET AL. analyzed.] Anogen
Page 185 and 186: 262 CHAPIN ET AL. purposeful confou
Page 187 and 188: 264 CHAPIN ET AL. increased lordosi
Page 189 and 190: 266 CHAPIN ET AL. that there was a
Page 191 and 192: 268 CHAPIN ET AL. duration of adver
Page 193 and 194: 270 CHAPIN ET AL. doses of potent e
Page 195 and 196: 272 CHAPIN ET AL. Table 74 Effects
Page 197 and 198: 274 CHAPIN ET AL. reproductive orga
Page 199 and 200: 276 CHAPIN ET AL. tyrosine-hydroxly
Page 201 and 202: 278 CHAPIN ET AL. include small sam
Page 203 and 204: 280 CHAPIN ET AL. males/group. [It
Page 205 and 206: 282 CHAPIN ET AL. termination, whic
Page 207 and 208: 284 CHAPIN ET AL. provided a reliab
Page 209 and 210: 286 CHAPIN ET AL. grooming, and out
Page 211 and 212: 288 CHAPIN ET AL. method of oral do
Page 213 and 214: 290 CHAPIN ET AL. reared by their d
Page 215 and 216: 292 CHAPIN ET AL. has been informed
Page 217 and 218: 294 CHAPIN ET AL. buffered paraform
Page 219 and 220: 296 CHAPIN ET AL. unit. Further, th
Page 221 and 222: 298 CHAPIN ET AL. PND 21 and housed
Page 223 and 224: 300 CHAPIN ET AL. Tando et al. (200
Page 225 and 226: 302 CHAPIN ET AL. Purina Certified
Page 227 and 228: 304 CHAPIN ET AL. high-doses of bis
Page 229 and 230: 306 CHAPIN ET AL. born to those dam
Page 231: 308 CHAPIN ET AL. average weight we
Page 235 and 236: 312 CHAPIN ET AL. used for extracti
Page 237 and 238: 314 CHAPIN ET AL. jar, and there we
Page 239 and 240: 316 CHAPIN ET AL. of testes and com
Page 241 and 242: 318 CHAPIN ET AL. differentiation o
Page 243 and 244: 320 CHAPIN ET AL. Table 81 Summary
Page 245 and 246: 322 CHAPIN ET AL. Table 82 Continue
Page 251 and 252: 328 CHAPIN ET AL. 600 mg/kg bw/day)
Page 253 and 254: 330 CHAPIN ET AL. (Nagao et al., 19
Page 255 and 256: 332 CHAPIN ET AL. antinuclear antib
Page 257 and 258: 334 CHAPIN ET AL. least 6 animals.
Page 259 and 260: 336 CHAPIN ET AL. Utility (Adequacy
Page 261 and 262: 338 CHAPIN ET AL. stomach weight wa
Page 263 and 264: 340 CHAPIN ET AL. Schirling et al.
Page 265 and 266: 342 CHAPIN ET AL. Endpoint Table 88
Page 267 and 268: 344 CHAPIN ET AL. different diets b
Page 269 and 270: 346 CHAPIN ET AL. with 40 mg vitami
Page 271 and 272: 348 CHAPIN ET AL. the bisphenol A v
Page 273 and 274: 350 CHAPIN ET AL. and determining t
Page 275 and 276: 352 CHAPIN ET AL. expression [to B6
Page 277 and 278: 354 CHAPIN ET AL. indicated] at 0 (
Page 279 and 280: 356 CHAPIN ET AL. concentrations us
Page 281 and 282: 358 CHAPIN ET AL. animals were non-
Page 283 and 284:
360 CHAPIN ET AL. following adjustm
Page 285 and 286:
362 CHAPIN ET AL. Table 94 Treatmen
Page 287 and 288:
364 CHAPIN ET AL. Table 97 Effects
Page 289 and 290:
366 CHAPIN ET AL. Table 99 Treatmen
Page 291 and 292:
368 CHAPIN ET AL. Therefore the NTP
Page 293 and 294:
370 CHAPIN ET AL. weeks before mati
Page 295 and 296:
372 CHAPIN ET AL. Table 100 Summary
Page 297 and 298:
374 Table 101 Summary of High Utili
Page 299 and 300:
376 Table 102 Summary of Limited Ut
Page 301 and 302:
378 CHAPIN ET AL. Table 103 Summary
Page 303 and 304:
380 CHAPIN ET AL. from other suppli
Page 305 and 306:
382 CHAPIN ET AL. U.S. populations.
Page 307 and 308:
384 CHAPIN ET AL. 10. Critical desi
Page 309 and 310:
386 CHAPIN ET AL. Engel SM, Levy B,
Page 311 and 312:
388 CHAPIN ET AL. alpha and beta ex
Page 313 and 314:
390 CHAPIN ET AL. Murray TJ, Maffin
Page 315 and 316:
392 CHAPIN ET AL. Ryan BC, Vandenbe
Page 317 and 318:
394 CHAPIN ET AL. Thomas P, Dong J.
Page 319 and 320:
Page 321:
appendix iii. publiC CommenTs and p
show all

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

Create successful ePaper yourself

Delete template?

Save as template?