- Email: [email protected]
Response to the comment on Viberg et al. (2008) “Neonatal ketamine exposure results in changes in biochemical substrates of neuronal growth and synaptogenesis, and alters adult behavior irreversibly” by Ching-Hung Hsu
154
Letter to the Editor / Toxicology 253 (2008) 153–154
References EPA, 2000. Benchmark dose technical guidance document. EPA/630/R-00/001, 1–87. Eriksson, P., et al., 2005. Developmental toxicology in the neonatal mouse: the use of randomly selected individuals as statistical unit compared to the litter in mice neonatally exposed to PBDE 99. The Toxicologist, Abstract No. 1074, 219–220. Eriksson, P., 2008. Response to: Use of the pup as the statistical unit in developmental neurotoxicity studies: overlooked model or poor research design? Toxicological Sciences 103, 411–413. Fischer, C., et al., 2008. Neonatal co-exposure to low doses of an ortho-PCB(PCB 153) and methyl mercury exacerbate defective developmental neurobehavior in mice. Toxicology 244, 157–165. Hardy, M., Stedeford, T., 2008. Developmental neurotoxicity in neonatal mice following co-exposure to PCB 153 and methyl mercury: interaction or false positive? Toxicology 248, 160–161. Holson, R.R., Pearce, B., 1992. Principles and pitfalls in the analysis of prenatal treatment effects in multiparous species. Neurotoxicology and Teratology 14, 221–228. Holson, R.R., et al., 2008. Statistical issues and techniques appropriate for developmental neurotoxicity testing A report from the ILSI Research Foundation/Risk Science Institute expert working group on neurodevelopmental endpoints. Neurotoxicology and Teratology 30, 326–348. OECD, 2007. Developmental neurotoxicity study. OECD Guidelines for the Testing of Chemicals #426, 1–26. Viberg, H., et al., 2008. Neonatal ketamine exposure results in changes in biochemical substrates of neuronal growth and synaptogenesis, and alters adult behavior irreversibly. Toxicology, doi:10.1016/j.tox.2008.04.019.
Ching-Hung Hsu ∗ Preclinical Development, TaiGen Biotechnology Co., Ltd., 7F, 138 Shin Ming Road, Neihu District, Taipei 114, Taiwan, ROC ∗ Tel.:
+886 2 8177 7072x1735; fax: +886 2 2796 3606. E-mail address: [email protected] 21 July 2008 Available online 22 August 2008
doi:10.1016/j.tox.2008.08.005
Response to the comment on Viberg et al. (2008) “Neonatal ketamine exposure results in changes in biochemical substrates of neuronal growth and synaptogenesis, and alters adult behavior irreversibly” by Ching-Hung Hsu The present topic has recently been up for debate in scientific journals (Eriksson, 2008a,b; Hardy and Stedeford, 2008a,b), all which apply the peer-review process, the quality assurance of the scientific community. During the past 20 years more than a 100 reviewers and statistical experts, as part of the peer-review process, have accepted the experimental design and evaluation of our data, leading to publication of more than 60 articles in scientific journals. What can be concluded is that there is a difference of opinions concerning what statistical evaluation should be used when directly dosing the newborn pups from a litter during the neonatal period, in contrast to dosing the dam in order to indirectly expose the offspring in utero and/or during the lactation period. When it comes to the well established use of ketamine as a developmental neurotoxicant, manifesting its toxicity as disturbed behavior and/or neurodegeneration, there are many studies published by different authors, from different laboratories, in different countries, using different types of statistical evaluations (Boctor et al., 2008; Fantel and Shepard, 2000; Ikonomidou et al., 2001; Majewski-Tiedeken et al., 2008; Olney, 2002; Olney et al., 2000; Scallet et al., 2004; Slikker et al., 2007). In addition, this is the fifth time our research group has published a study showing that ketamine can affect adult behavior after neonatal exposure (Fredriksson and Archer, 2003, 2004; Fredriksson et al.,
2004; Fredriksson et al., 2007). All the above-mentioned studies have been reviewed by experts in the field as part of the peerreview process applied by the scientific journals, some which have their own statistical experts. Furthermore, our research does not attempt to follow EPA or OECD guidelines, but is instead basic science, which is very much needed in order increase the knowledge about neurotoxic processes and mechanisms. Conflict of interest None. References Boctor, S.Y., Wang, C., Ferguson, S.A., 2008. Neonatal PCP is more potent than ketamine at modifying preweaning behaviors of Sprague–Dawley rats. Toxicol. Sci.. Eriksson, P., 2008a. Reply to the letter to the editor. Toxicology 248, 162–163. Eriksson, P., 2008b. Response to: use of the pup as the statistical unit in developmental neurotoxicity studies: overlooked model or poor research design? Toxicol. Sci. 103, 411–413. Fantel, A.G., Shepard, T.H., 2000. Potential role of maternal toxicity in the developmental effects of ketamine and cocaine in mice. Teratology 62, 177. Fredriksson, A., Archer, T., 2003. Hyperactivity following postnatal NMDA antagonist treatment: reversal by d-amphetamine. Neurotox. Res. 5, 549–564. Fredriksson, A., Archer, T., 2004. Neurobehavioural deficits associated with apoptotic neurodegeneration and vulnerability for ADHD. Neurotox. Res. 6, 435–456. Fredriksson, A., Archer, T., Alm, H., Gordh, T., Eriksson, P., 2004. Neurofunctional deficits and potentiated apoptosis by neonatal NMDA antagonist administration. Behav. Brain Res. 153, 367–376. Fredriksson, A., Ponten, E., Gordh, T., Eriksson, P., 2007. Neonatal exposure to a combination of N-methyl-d-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology 107, 427–436. Hardy, M., Stedeford, T., 2008a. Use of the pup as the statistical unit in developmental neurotoxicity studies: overlooked model or poor research design? Toxicol. Sci. 103, 409–410. Hardy, M.L., Stedeford, T., 2008b. Developmental neurotoxicity in neonatal mice following co-exposure to PCB 153 and methyl mercury: interaction or false positive? Toxicology 248, 160–161 (author reply 162–163). Ikonomidou, C., Bittigau, P., Koch, C., Genz, K., Hoerster, F., Felderhoff-Mueser, U., Tenkova, T., Dikranian, K., Olney, J.W., 2001. Neurotransmitters and apoptosis in the developing brain. Biochem. Pharmacol. 62, 401–405. Majewski-Tiedeken, C.R., Rabin, C.R., Siegel, S.J., 2008. Ketamine exposure in adult mice leads to increased cell death in C3H. DBA2 and FVB inbred mouse strains. Drug Alcohol Depend. 92, 217–227. Olney, J.W., 2002. New insights and new issues in developmental neurotoxicology. Neurotoxicology 23, 659–668. Olney, J.W., Farber, N.B., Wozniak, D.F., Jevtovic-Todorovic, V., Ikonomidou, C., 2000. Environmental agents that have the potential to trigger massive apoptotic neurodegeneration in the developing brain. Environ. Health Perspect. 108 (Suppl. 3), 383–388. Scallet, A.C., Schmued, L.C., Slikker Jr., W., Grunberg, N., Faustino, P.J., Davis, H., Lester, D., Pine, P.S., Sistare, F., Hanig, J.P., 2004. Developmental neurotoxicity of ketamine: morphometric confirmation, exposure parameters, and multiple fluorescent labeling of apoptotic neurons. Toxicol. Sci. 81, 364–370. Slikker Jr., W., Zou, X., Hotchkiss, C.E., Divine, R.L., Sadovova, N., Twaddle, N.C., Doerge, D.R., Scallet, A.C., Patterson, T.A., Hanig, J.P., Paule, M.G., Wang, C., 2007. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol. Sci. 98, 145–158.
Henrik Viberg ∗ Department of Environmental Toxicology, Uppsala University, 75236 Uppsala, Sweden ∗ Tel.: +46 184717695. E-mail address: [email protected]
15 August 2008 Available online 22 August 2008 doi:10.1016/j.tox.2008.08.006
Letter to the Editor / Toxicology 253 (2008) 153–154
References EPA, 2000. Benchmark dose technical guidance document. EPA/630/R-00/001, 1–87. Eriksson, P., et al., 2005. Developmental toxicology in the neonatal mouse: the use of randomly selected individuals as statistical unit compared to the litter in mice neonatally exposed to PBDE 99. The Toxicologist, Abstract No. 1074, 219–220. Eriksson, P., 2008. Response to: Use of the pup as the statistical unit in developmental neurotoxicity studies: overlooked model or poor research design? Toxicological Sciences 103, 411–413. Fischer, C., et al., 2008. Neonatal co-exposure to low doses of an ortho-PCB(PCB 153) and methyl mercury exacerbate defective developmental neurobehavior in mice. Toxicology 244, 157–165. Hardy, M., Stedeford, T., 2008. Developmental neurotoxicity in neonatal mice following co-exposure to PCB 153 and methyl mercury: interaction or false positive? Toxicology 248, 160–161. Holson, R.R., Pearce, B., 1992. Principles and pitfalls in the analysis of prenatal treatment effects in multiparous species. Neurotoxicology and Teratology 14, 221–228. Holson, R.R., et al., 2008. Statistical issues and techniques appropriate for developmental neurotoxicity testing A report from the ILSI Research Foundation/Risk Science Institute expert working group on neurodevelopmental endpoints. Neurotoxicology and Teratology 30, 326–348. OECD, 2007. Developmental neurotoxicity study. OECD Guidelines for the Testing of Chemicals #426, 1–26. Viberg, H., et al., 2008. Neonatal ketamine exposure results in changes in biochemical substrates of neuronal growth and synaptogenesis, and alters adult behavior irreversibly. Toxicology, doi:10.1016/j.tox.2008.04.019.
Ching-Hung Hsu ∗ Preclinical Development, TaiGen Biotechnology Co., Ltd., 7F, 138 Shin Ming Road, Neihu District, Taipei 114, Taiwan, ROC ∗ Tel.:
+886 2 8177 7072x1735; fax: +886 2 2796 3606. E-mail address: [email protected] 21 July 2008 Available online 22 August 2008
doi:10.1016/j.tox.2008.08.005
Response to the comment on Viberg et al. (2008) “Neonatal ketamine exposure results in changes in biochemical substrates of neuronal growth and synaptogenesis, and alters adult behavior irreversibly” by Ching-Hung Hsu The present topic has recently been up for debate in scientific journals (Eriksson, 2008a,b; Hardy and Stedeford, 2008a,b), all which apply the peer-review process, the quality assurance of the scientific community. During the past 20 years more than a 100 reviewers and statistical experts, as part of the peer-review process, have accepted the experimental design and evaluation of our data, leading to publication of more than 60 articles in scientific journals. What can be concluded is that there is a difference of opinions concerning what statistical evaluation should be used when directly dosing the newborn pups from a litter during the neonatal period, in contrast to dosing the dam in order to indirectly expose the offspring in utero and/or during the lactation period. When it comes to the well established use of ketamine as a developmental neurotoxicant, manifesting its toxicity as disturbed behavior and/or neurodegeneration, there are many studies published by different authors, from different laboratories, in different countries, using different types of statistical evaluations (Boctor et al., 2008; Fantel and Shepard, 2000; Ikonomidou et al., 2001; Majewski-Tiedeken et al., 2008; Olney, 2002; Olney et al., 2000; Scallet et al., 2004; Slikker et al., 2007). In addition, this is the fifth time our research group has published a study showing that ketamine can affect adult behavior after neonatal exposure (Fredriksson and Archer, 2003, 2004; Fredriksson et al.,
2004; Fredriksson et al., 2007). All the above-mentioned studies have been reviewed by experts in the field as part of the peerreview process applied by the scientific journals, some which have their own statistical experts. Furthermore, our research does not attempt to follow EPA or OECD guidelines, but is instead basic science, which is very much needed in order increase the knowledge about neurotoxic processes and mechanisms. Conflict of interest None. References Boctor, S.Y., Wang, C., Ferguson, S.A., 2008. Neonatal PCP is more potent than ketamine at modifying preweaning behaviors of Sprague–Dawley rats. Toxicol. Sci.. Eriksson, P., 2008a. Reply to the letter to the editor. Toxicology 248, 162–163. Eriksson, P., 2008b. Response to: use of the pup as the statistical unit in developmental neurotoxicity studies: overlooked model or poor research design? Toxicol. Sci. 103, 411–413. Fantel, A.G., Shepard, T.H., 2000. Potential role of maternal toxicity in the developmental effects of ketamine and cocaine in mice. Teratology 62, 177. Fredriksson, A., Archer, T., 2003. Hyperactivity following postnatal NMDA antagonist treatment: reversal by d-amphetamine. Neurotox. Res. 5, 549–564. Fredriksson, A., Archer, T., 2004. Neurobehavioural deficits associated with apoptotic neurodegeneration and vulnerability for ADHD. Neurotox. Res. 6, 435–456. Fredriksson, A., Archer, T., Alm, H., Gordh, T., Eriksson, P., 2004. Neurofunctional deficits and potentiated apoptosis by neonatal NMDA antagonist administration. Behav. Brain Res. 153, 367–376. Fredriksson, A., Ponten, E., Gordh, T., Eriksson, P., 2007. Neonatal exposure to a combination of N-methyl-d-aspartate and gamma-aminobutyric acid type A receptor anesthetic agents potentiates apoptotic neurodegeneration and persistent behavioral deficits. Anesthesiology 107, 427–436. Hardy, M., Stedeford, T., 2008a. Use of the pup as the statistical unit in developmental neurotoxicity studies: overlooked model or poor research design? Toxicol. Sci. 103, 409–410. Hardy, M.L., Stedeford, T., 2008b. Developmental neurotoxicity in neonatal mice following co-exposure to PCB 153 and methyl mercury: interaction or false positive? Toxicology 248, 160–161 (author reply 162–163). Ikonomidou, C., Bittigau, P., Koch, C., Genz, K., Hoerster, F., Felderhoff-Mueser, U., Tenkova, T., Dikranian, K., Olney, J.W., 2001. Neurotransmitters and apoptosis in the developing brain. Biochem. Pharmacol. 62, 401–405. Majewski-Tiedeken, C.R., Rabin, C.R., Siegel, S.J., 2008. Ketamine exposure in adult mice leads to increased cell death in C3H. DBA2 and FVB inbred mouse strains. Drug Alcohol Depend. 92, 217–227. Olney, J.W., 2002. New insights and new issues in developmental neurotoxicology. Neurotoxicology 23, 659–668. Olney, J.W., Farber, N.B., Wozniak, D.F., Jevtovic-Todorovic, V., Ikonomidou, C., 2000. Environmental agents that have the potential to trigger massive apoptotic neurodegeneration in the developing brain. Environ. Health Perspect. 108 (Suppl. 3), 383–388. Scallet, A.C., Schmued, L.C., Slikker Jr., W., Grunberg, N., Faustino, P.J., Davis, H., Lester, D., Pine, P.S., Sistare, F., Hanig, J.P., 2004. Developmental neurotoxicity of ketamine: morphometric confirmation, exposure parameters, and multiple fluorescent labeling of apoptotic neurons. Toxicol. Sci. 81, 364–370. Slikker Jr., W., Zou, X., Hotchkiss, C.E., Divine, R.L., Sadovova, N., Twaddle, N.C., Doerge, D.R., Scallet, A.C., Patterson, T.A., Hanig, J.P., Paule, M.G., Wang, C., 2007. Ketamine-induced neuronal cell death in the perinatal rhesus monkey. Toxicol. Sci. 98, 145–158.
Henrik Viberg ∗ Department of Environmental Toxicology, Uppsala University, 75236 Uppsala, Sweden ∗ Tel.: +46 184717695. E-mail address: [email protected]
15 August 2008 Available online 22 August 2008 doi:10.1016/j.tox.2008.08.006