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Long-term cognitive effects of low-level developmental organophosphate pesticide exposure: Divergent effects of chlorpyrifos, diazinon and parathion
M. Stanton et al. / Neurotoxicology and Teratology 30 (2008) 243–259
NTBS26 Correspondence between experimental and epidemiological findings: How good is it? Deborah Rice Maine Center for Disease Control and Prevention, United States
Screening tests are adequate to identify a chemical as neurotoxic at some dose, which may not be environmentally relevant. Of more interest and importance is the ability of experimental studies to predict the functional domains impaired by a particular neurotoxicant, and the degree to which appropriate toxicity values (e.g., RfDs) can be derived from experimental data. Answers to both of these questions necessarily rely on having data from both human and animal studies for comparison. Perhaps the two best-studied chemicals are the metals lead and methylmercury. It is clear that lead produces impairment in cognitive function on numerous tasks, decreased attention, increased impulsivity, and problems in sensory processing in both animals and children. There is a good correspondence between humans and animals with respect to the body burden at which toxicity is observed, whereas external dose may not be a good predictor. For methylmercury, the ability of animal studies to predict effects in children may be dose- and species-dependent, perhaps in part as a result of differential kinetics. For pesticides, there is a much less detailed literature, either with respect to epidemiological studies documenting the pattern of functional impairment in children or animals, or the body burdens at which they occur. doi:10.1016/j.ntt.2008.03.029
NBTS27 Developmental pesticide exposure: A new risk factor for ADHD? Jason Richardson Robert Wood Johnson Medical School, United States
Attention-deficit hyperactivity disorder (ADHD) is estimated to affect 8–12% of school-aged children worldwide. Although there is a significant genetic component to ADHD, no single gene has been linked to a significant percentage of cases, suggesting a role for environmental factors in ADHD. Recent data from my laboratory suggest that pesticide exposure may be a risk factor for ADHD. Mice exposed during development to the pyrethroid pesticide deltamethrin exhibit symptoms similar to those observed in children with ADHD, including elevated dopamine transporter (DAT) levels, hyperactivity, impulsive-like behavior, and a paradoxical calming response to methylphenidate (Ritalin). Data reveal that deltamethrin interacts with Na+ channels to cause persistent depolarization and increased transcription of Nurr1 and Pitx3 transcription factors. This leads to an increased expression of the DAT, which in turn causes increased levels of the D1 dopamine receptor that contributes to the behavioral deficits observed. To determine whether our laboratory findings were supported by observations in the human population, we carried out a cross-sectional study of pyrethroid pesticide exposure as a risk factor of ADHD using data from the National Health and Nutrition Examination Survey. Parents of children aged 6–15 with detectable levels of pyrethroid metabolites in their urine were more than twice as likely to report that a doctor or health
251
professional had told them their child had ADHD. The parallels between mice developmentally exposed to deltamethrin and individuals with ADHD reinforce the epidemiological data suggesting that developmental pesticide exposure is a risk factor for ADHD. doi:10.1016/j.ntt.2008.03.030
NBTS28 Long-term cognitive effects of low-level developmental organophosphate pesticide exposure: Divergent effects of chlorpyrifos, diazinon and parathion Edward Levin, Olga Timofeeva, Frederic Seidler, Theodore Slotkin Duke University, United States
Organophosphate (OP) pesticides all share the ability to inhibit cholinesterase which is responsible for high dose systemic toxicity and used to set “safe” exposure limits. However, recent research demonstrates that OPs cause developmental neurotoxicity at doses below those that inhibit cholinesterase. Because this involves mechanisms other than the shared property of cholinesterase inhibition, different OPs are likely to have disparate low dose effects. In rats, we compared persistent neurocognitive effects of neonatal (PND 1–4) exposure to chlorpyrifos, diazinon or parathion at doses below and just above the threshold for detectable cholinesterase inhibition. Each agent caused significant persisting effects in adulthood on the radialarm maze but effects with each agent differed. Chlorpyrifos caused a sex-selective working memory effect, with males showing a significant increase in errors and females showing a significant decrease, eliminating the normal sex difference in spatial discrimination. Postnatal diazinon significantly impaired working memory without regard to sex. Parathion during the same period caused a significant reduction in working memory errors, without regard to sex. Similarly, for cognitive effects of cholinergic and serotonergic antagonist challenges and tests of emotionality, low doses of each agent produced different spectra of persisting effects. Our studies show that apparently “safe” developmental OP exposures nevertheless cause persistent behavioral effects that differ among the various agents. Mechanisms other than cholinesterase inhibition contribute to the developmental neurotoxicity of OPs and need to be considered in setting exposure limits. The disparate actions provide key information to identify, which OPs may pose greater neurotoxic risk. doi:10.1016/j.ntt.2008.03.031
NBTS29 The efficacy of succimer chelation in an animal model of pediatric lead exposure Barbara Strupp a, Diane Stangle a, Myla Strawderman a, Stephane Beaudin a, Donald Smith b a Cornell University, United States b University of California at Santa Cruz, United States
In light of growing evidence that even slightly elevated lead levels can lead to lasting cognitive and behavioral alterations, there is pressure to administer chelating agents to children with
NTBS26 Correspondence between experimental and epidemiological findings: How good is it? Deborah Rice Maine Center for Disease Control and Prevention, United States
Screening tests are adequate to identify a chemical as neurotoxic at some dose, which may not be environmentally relevant. Of more interest and importance is the ability of experimental studies to predict the functional domains impaired by a particular neurotoxicant, and the degree to which appropriate toxicity values (e.g., RfDs) can be derived from experimental data. Answers to both of these questions necessarily rely on having data from both human and animal studies for comparison. Perhaps the two best-studied chemicals are the metals lead and methylmercury. It is clear that lead produces impairment in cognitive function on numerous tasks, decreased attention, increased impulsivity, and problems in sensory processing in both animals and children. There is a good correspondence between humans and animals with respect to the body burden at which toxicity is observed, whereas external dose may not be a good predictor. For methylmercury, the ability of animal studies to predict effects in children may be dose- and species-dependent, perhaps in part as a result of differential kinetics. For pesticides, there is a much less detailed literature, either with respect to epidemiological studies documenting the pattern of functional impairment in children or animals, or the body burdens at which they occur. doi:10.1016/j.ntt.2008.03.029
NBTS27 Developmental pesticide exposure: A new risk factor for ADHD? Jason Richardson Robert Wood Johnson Medical School, United States
Attention-deficit hyperactivity disorder (ADHD) is estimated to affect 8–12% of school-aged children worldwide. Although there is a significant genetic component to ADHD, no single gene has been linked to a significant percentage of cases, suggesting a role for environmental factors in ADHD. Recent data from my laboratory suggest that pesticide exposure may be a risk factor for ADHD. Mice exposed during development to the pyrethroid pesticide deltamethrin exhibit symptoms similar to those observed in children with ADHD, including elevated dopamine transporter (DAT) levels, hyperactivity, impulsive-like behavior, and a paradoxical calming response to methylphenidate (Ritalin). Data reveal that deltamethrin interacts with Na+ channels to cause persistent depolarization and increased transcription of Nurr1 and Pitx3 transcription factors. This leads to an increased expression of the DAT, which in turn causes increased levels of the D1 dopamine receptor that contributes to the behavioral deficits observed. To determine whether our laboratory findings were supported by observations in the human population, we carried out a cross-sectional study of pyrethroid pesticide exposure as a risk factor of ADHD using data from the National Health and Nutrition Examination Survey. Parents of children aged 6–15 with detectable levels of pyrethroid metabolites in their urine were more than twice as likely to report that a doctor or health
251
professional had told them their child had ADHD. The parallels between mice developmentally exposed to deltamethrin and individuals with ADHD reinforce the epidemiological data suggesting that developmental pesticide exposure is a risk factor for ADHD. doi:10.1016/j.ntt.2008.03.030
NBTS28 Long-term cognitive effects of low-level developmental organophosphate pesticide exposure: Divergent effects of chlorpyrifos, diazinon and parathion Edward Levin, Olga Timofeeva, Frederic Seidler, Theodore Slotkin Duke University, United States
Organophosphate (OP) pesticides all share the ability to inhibit cholinesterase which is responsible for high dose systemic toxicity and used to set “safe” exposure limits. However, recent research demonstrates that OPs cause developmental neurotoxicity at doses below those that inhibit cholinesterase. Because this involves mechanisms other than the shared property of cholinesterase inhibition, different OPs are likely to have disparate low dose effects. In rats, we compared persistent neurocognitive effects of neonatal (PND 1–4) exposure to chlorpyrifos, diazinon or parathion at doses below and just above the threshold for detectable cholinesterase inhibition. Each agent caused significant persisting effects in adulthood on the radialarm maze but effects with each agent differed. Chlorpyrifos caused a sex-selective working memory effect, with males showing a significant increase in errors and females showing a significant decrease, eliminating the normal sex difference in spatial discrimination. Postnatal diazinon significantly impaired working memory without regard to sex. Parathion during the same period caused a significant reduction in working memory errors, without regard to sex. Similarly, for cognitive effects of cholinergic and serotonergic antagonist challenges and tests of emotionality, low doses of each agent produced different spectra of persisting effects. Our studies show that apparently “safe” developmental OP exposures nevertheless cause persistent behavioral effects that differ among the various agents. Mechanisms other than cholinesterase inhibition contribute to the developmental neurotoxicity of OPs and need to be considered in setting exposure limits. The disparate actions provide key information to identify, which OPs may pose greater neurotoxic risk. doi:10.1016/j.ntt.2008.03.031
NBTS29 The efficacy of succimer chelation in an animal model of pediatric lead exposure Barbara Strupp a, Diane Stangle a, Myla Strawderman a, Stephane Beaudin a, Donald Smith b a Cornell University, United States b University of California at Santa Cruz, United States
In light of growing evidence that even slightly elevated lead levels can lead to lasting cognitive and behavioral alterations, there is pressure to administer chelating agents to children with