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Behavioral outcome in children exposed prenatally to lamotrigine, valproate, or carbamazepine: Increased risks for valproate
NBTS 2010 Abstract
NBTS45 Behavioral outcome in children exposed prenatally to lamotrigine, valproate, or carbamazepine: Increased risks for valproate Uma Deshmukha, Jane Adamsb, Ruby Dhillona, Katherine McCarthya, Eric Macklina, Lewis Holmesa,c a Massachusetts General Hospital, Boston, MA, United States b University of Massachusetts Boston, Boston, MA, United States c Harvard Medical School, Boston, MA, United States Recent studies have raised concerns about the cognitive effects of fetal exposure to anticonvulsant drugs. We present a study investigating adaptive behavior characteristics of children exposed prenatally to lamotrigine (LTG), valproate (VPA), or carbamazepine (CBZ) monotherapies. Data were collected from women enrolled in the North American Antiepileptic Drug Pregnancy Registry who had taken LTG, VPA, or CBZ throughout pregnancy to suppress seizures. All participants had children 36 to 83 months of age who were exposed to anticonvulsant monotherapy throughout gestation. Adaptive behavior of 254 children (101 CBZ-exposed, 103 LTGexposed, and 50 VPA-exposed) was measured using the Vineland-II Adaptive Behavior Scales, administered by telephone with the child's mother. Mean adaptive behavior composite (ABC) and domain standard scores for communication, daily living, socialization, and motor skills were analyzed for each drug group. VPA-exposed children had lower mean standard scores than those exposed to LTG or CBZ for composite and domain scores. The mean ABC score for VPA-exposed children was 94.3 ± 16.4 versus 100.6 ± 10.1 for CBZexposed and 103.0 ± 11.0 for LTG-exposed children (ANOVA; p = 0.003). The prevalence of low or below average ABC scores was significantly greater in VPA-exposed children (20%) than children exposed to CBZ (5.9%) or LTG (2.9%) (Chi-square; p < 0.001). VPA-exposed children were more likely to score low or below average in the socialization and motor domains. These findings indicate increased risk for adaptive behavior impairments and autism spectrum disorder among children prenatally exposed to VPA. This study was supported by GlaxoSmithKline. Current Registry sponsors include Abbott, Eisai, Ortho-McNeil, Novartis, Pfizer and Sepracor.
doi:10.1016/j.ntt.2010.04.046
NBTS46 Effects of age of exposure to 3,4-methylenedioxymethamphetamine (MDMA) in rats on later learning and behavior Charles Vorhees, Matthew Skelton, Devon Graham, Tori Schaefer, Curtis Grace, Amanda Braun, Michael Williams Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States Previous findings showed allocentric and egocentric learning deficits after MDMA treatment from P11–20 but not after treatment from P1–10. Shorter treatment periods (P1–5, 6–10, 11–15, or 16–20) resulted in allocentric learning deficits across intervals, but none caused egocentric learning deficits. Whether this difference was attributable to treatment length or age at the start of treatment was unclear. Accordingly, in the present experiment litters were treated on P1–10, 6–15, or 11–20 with 0, 10, or 15 mg/kg MDMA × 4 at 2 h intervals. Two male/female pairs/litter received each treatment. One pair/group/litter received acoustic startle/PPI, straight channel swimming, Cincinnati water maze (CWM), and conditioned fear in a latent
509
inhibition paradigm. The other pair/group/litter received locomotor activity, straight channel swimming, Morris water maze (MWM), and locomotor activity with MK-801 challenge. MDMA impaired CWM and MWM (acquisition phase), but the effects after P1–10 exposure were smaller than those after P6–15 or 11–20 exposure whereas on MWM reversal and shift, only the P6–15 and 11–20 MDMA offspring were significantly impaired. The largest activity reductions were evident after P6–15 treatment while the largest acoustic startle increases were evident after P1–10 treatment. Swim speed was unaffected for all exposure periods. After MK-801 challenge, MDMAtreated offspring under-responded compared to saline-treated offspring. Brain monoamines were also altered. The results show that no single critical period exists for MDMA but rather overlapping periods that are most likely related to differences in rates of regional brain development. (Supported by DA021394 and ES07051.)
doi:10.1016/j.ntt.2010.04.047
NBTS47 Predicting the acute behavioral effects in rats inhaling toluene for up to 24 h: Inhaled vs. internal dose metrics and tolerance W.M. Oshiro, Q.T. Krantz, C.J. Gordon, E.M. Kenyon, P.J. Bushnell US Environmental Protection Agency, Office of Research and Development, National Health Effects and Environmental Research Laboratory, Research Triangle Park, NC, United States The acute toxicity of toluene, a model volatile organic compound (VOC), depends on the concentration (C) and duration (t) of exposure, and guidelines for acute exposures have traditionally used C × t relationships to extrapolate protective and/or effective concentrations across durations of exposure. Recent research suggests an alternative approach for duration adjustment, which uses PBPK model-derived estimates of internal dose as the basis for duration extrapolation. For example, acute behavioral effects observed in rats performing a visual signal detection task (SDT) while being exposed to common VOCs (including toluene) for up to 1 h are better predicted by the momentary concentration of the VOC in the brain at the time of the observed effect than by the C × t product. The current study was designed to compare the ability of the two approaches to predict acute effects incurred during exposures to toluene lasting up to 24 h. Thus, 16 male, Long–Evans rats were trained to perform the SDT, and then were exposed to toluene at concentrations of 0, 1125 and 1450 ppm for 24 h and to 1660 ppm for 21 h. During each exposure the animals were tested at times predetermined to yield comparable C × t products (2900, 8700, 27,000 and 34,800 ppm h) but differing estimates of brain toluene concentrations (estimated by a PBPK model to range from 80 to 140 mg/L). Results showed that toluene reduced accuracy and increased response time, and these effects were better predicted by the brain toluene concentration than by either the inhaled C or C × t product of exposure. Nevertheless, effects of 24-h exposures were far less severe than effects of 1-h exposures, even when gauged against the estimated concentration of toluene in the brain. Thus, whereas use of an internal dose metric improved prediction of acute behavioral effects of toluene, this metric did not improve the accuracy of extrapolating from short- to longduration exposures, which was complicated by the development of both metabolic and behavioral tolerance to the acute effects of toluene. (This abstract does not necessarily reflect EPA policy.)
doi:10.1016/j.ntt.2010.04.048
NBTS45 Behavioral outcome in children exposed prenatally to lamotrigine, valproate, or carbamazepine: Increased risks for valproate Uma Deshmukha, Jane Adamsb, Ruby Dhillona, Katherine McCarthya, Eric Macklina, Lewis Holmesa,c a Massachusetts General Hospital, Boston, MA, United States b University of Massachusetts Boston, Boston, MA, United States c Harvard Medical School, Boston, MA, United States Recent studies have raised concerns about the cognitive effects of fetal exposure to anticonvulsant drugs. We present a study investigating adaptive behavior characteristics of children exposed prenatally to lamotrigine (LTG), valproate (VPA), or carbamazepine (CBZ) monotherapies. Data were collected from women enrolled in the North American Antiepileptic Drug Pregnancy Registry who had taken LTG, VPA, or CBZ throughout pregnancy to suppress seizures. All participants had children 36 to 83 months of age who were exposed to anticonvulsant monotherapy throughout gestation. Adaptive behavior of 254 children (101 CBZ-exposed, 103 LTGexposed, and 50 VPA-exposed) was measured using the Vineland-II Adaptive Behavior Scales, administered by telephone with the child's mother. Mean adaptive behavior composite (ABC) and domain standard scores for communication, daily living, socialization, and motor skills were analyzed for each drug group. VPA-exposed children had lower mean standard scores than those exposed to LTG or CBZ for composite and domain scores. The mean ABC score for VPA-exposed children was 94.3 ± 16.4 versus 100.6 ± 10.1 for CBZexposed and 103.0 ± 11.0 for LTG-exposed children (ANOVA; p = 0.003). The prevalence of low or below average ABC scores was significantly greater in VPA-exposed children (20%) than children exposed to CBZ (5.9%) or LTG (2.9%) (Chi-square; p < 0.001). VPA-exposed children were more likely to score low or below average in the socialization and motor domains. These findings indicate increased risk for adaptive behavior impairments and autism spectrum disorder among children prenatally exposed to VPA. This study was supported by GlaxoSmithKline. Current Registry sponsors include Abbott, Eisai, Ortho-McNeil, Novartis, Pfizer and Sepracor.
doi:10.1016/j.ntt.2010.04.046
NBTS46 Effects of age of exposure to 3,4-methylenedioxymethamphetamine (MDMA) in rats on later learning and behavior Charles Vorhees, Matthew Skelton, Devon Graham, Tori Schaefer, Curtis Grace, Amanda Braun, Michael Williams Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States Previous findings showed allocentric and egocentric learning deficits after MDMA treatment from P11–20 but not after treatment from P1–10. Shorter treatment periods (P1–5, 6–10, 11–15, or 16–20) resulted in allocentric learning deficits across intervals, but none caused egocentric learning deficits. Whether this difference was attributable to treatment length or age at the start of treatment was unclear. Accordingly, in the present experiment litters were treated on P1–10, 6–15, or 11–20 with 0, 10, or 15 mg/kg MDMA × 4 at 2 h intervals. Two male/female pairs/litter received each treatment. One pair/group/litter received acoustic startle/PPI, straight channel swimming, Cincinnati water maze (CWM), and conditioned fear in a latent
509
inhibition paradigm. The other pair/group/litter received locomotor activity, straight channel swimming, Morris water maze (MWM), and locomotor activity with MK-801 challenge. MDMA impaired CWM and MWM (acquisition phase), but the effects after P1–10 exposure were smaller than those after P6–15 or 11–20 exposure whereas on MWM reversal and shift, only the P6–15 and 11–20 MDMA offspring were significantly impaired. The largest activity reductions were evident after P6–15 treatment while the largest acoustic startle increases were evident after P1–10 treatment. Swim speed was unaffected for all exposure periods. After MK-801 challenge, MDMAtreated offspring under-responded compared to saline-treated offspring. Brain monoamines were also altered. The results show that no single critical period exists for MDMA but rather overlapping periods that are most likely related to differences in rates of regional brain development. (Supported by DA021394 and ES07051.)
doi:10.1016/j.ntt.2010.04.047
NBTS47 Predicting the acute behavioral effects in rats inhaling toluene for up to 24 h: Inhaled vs. internal dose metrics and tolerance W.M. Oshiro, Q.T. Krantz, C.J. Gordon, E.M. Kenyon, P.J. Bushnell US Environmental Protection Agency, Office of Research and Development, National Health Effects and Environmental Research Laboratory, Research Triangle Park, NC, United States The acute toxicity of toluene, a model volatile organic compound (VOC), depends on the concentration (C) and duration (t) of exposure, and guidelines for acute exposures have traditionally used C × t relationships to extrapolate protective and/or effective concentrations across durations of exposure. Recent research suggests an alternative approach for duration adjustment, which uses PBPK model-derived estimates of internal dose as the basis for duration extrapolation. For example, acute behavioral effects observed in rats performing a visual signal detection task (SDT) while being exposed to common VOCs (including toluene) for up to 1 h are better predicted by the momentary concentration of the VOC in the brain at the time of the observed effect than by the C × t product. The current study was designed to compare the ability of the two approaches to predict acute effects incurred during exposures to toluene lasting up to 24 h. Thus, 16 male, Long–Evans rats were trained to perform the SDT, and then were exposed to toluene at concentrations of 0, 1125 and 1450 ppm for 24 h and to 1660 ppm for 21 h. During each exposure the animals were tested at times predetermined to yield comparable C × t products (2900, 8700, 27,000 and 34,800 ppm h) but differing estimates of brain toluene concentrations (estimated by a PBPK model to range from 80 to 140 mg/L). Results showed that toluene reduced accuracy and increased response time, and these effects were better predicted by the brain toluene concentration than by either the inhaled C or C × t product of exposure. Nevertheless, effects of 24-h exposures were far less severe than effects of 1-h exposures, even when gauged against the estimated concentration of toluene in the brain. Thus, whereas use of an internal dose metric improved prediction of acute behavioral effects of toluene, this metric did not improve the accuracy of extrapolating from short- to longduration exposures, which was complicated by the development of both metabolic and behavioral tolerance to the acute effects of toluene. (This abstract does not necessarily reflect EPA policy.)
doi:10.1016/j.ntt.2010.04.048