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H A Tilson

Publications and source records attributed to H A Tilson.

At least 37 records · Page 2Linked to original sources
PubMed1997

Neurochemical effects of polychlorinated biphenyls: an overview and identification of research needs.

The PCBs are members of the halogenated hydrocarbon class of environmental chemicals that includes the dibenzofurans and dioxins. The PCBs were used over a period of 40 years for number of industrial purposes. Their appearance in the ecosystem and biological samples from wildlife, as well as documented cases of accidental poisoning led to the banning of their manufacture in 1977. The PCBs continue to be of concern to environmental toxicologists because of their persistence in the environment and reports that exposure to relatively low levels may be associated with subtle behavioral and neurological deficits, particularly if exposure occurs during development. Developmental neurotoxicity of PCBs has been reported in humans and confirmed in several laboratory animal species, including non-human primates. During the last 20 years, there has been an attempt to understand the cellular bases of PCB-induced behavioral and neurological effects in animal models. Exposure of adult animals to a single, relatively high dose of PCBs decreases the content of several brain neurotransmitters, while repeated exposure to lower PCB doses appears to affect brain DA metabolism. The mechanism by which PCB affects DA remains unclear. It is now known that some PCB congeners have a structural configuration that facilitates binding to an aryl hydrocarbon (Ah) receptor like other polychlorinated compounds, including 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Some PCB congeners, on the other hand, have structural characteristics, e.g., non-coplanarity, that diminish access to the Ah receptor. Non-TCDD-like PCB congeners that appear in the brain following in vivo exposure demonstrate the highest potency in terms of decreasing DA content in PC-12 cells and inhibiting calcium homeostasis mechanisms in vitro. The biological significance of the effects of the PCBs on DA content or calcium homeostasis with regard to the behavioral and neurological effects observed following developmental exposure in vivo is not clear. Recent research, however, suggests that PCBs can alter a number of physiological processes that may be important for development. For example, PCB-induced alterations in thyroid function during development may underlie some of the developmental effects of PCBs reported in humans and animal models. Additional research on the PCBs seems warranted in a number of areas, including the: 1) structural requirements necessary for binding to the Ah-receptor, 2) mechanism(s) of PCB-induced alterations in DA content and calcium homeostasis in vitro, 3) relationship between observed neurochemical effects in vitro and effects in vivo, and 4) relationship between PCB-induced neurochemical effects and crucial developmental processes such as those controlled by thyroid hormone development.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening. I. Background and genesis.

Numerous events over several years culminated in recognition of the need to explicitly evaluate the nervous system as a potential target for environmental chemicals. Based on recommendations from several international expert panels, the International Programme on Chemical Safety (IPCS) sponsored the Collaborative Study on Neurobehavioral Screening Methods. A Steering Committee was created to oversee the project, develop the testing protocol, recruit participating laboratories and review and analyze the data. The protocol specified the tests, the chemicals (supplied from a common source) and the exposure conditions (acute and repeated dosing). Test methods were based upon existing practices in toxicological screening as well as recent advances in neurotoxicity screening. Chemicals were selected to produce different profiles of neurobehavioral effects. Considerable latitude was afforded the participating laboratories in the choice of several key variables (e.g., strain of rat, testing device for motor activity assessment) that could potentially affect the results of the experiments. The approach therefore provided a standardized yet flexible protocol for evaluating the reproducibility of neurobehavioral screening data in diverse laboratory settings.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: II. Protocol design and testing procedures.

This paper describes the development of the protocol for the International Programme on Chemical Safety (IPCS)-sponsored Collaborative Study on Neurobehavioral Screening Methods, including background on the methods and chemicals selected, as well as details concerning the conduct of the collaborative study, including proficiency testing, range-finding and main study. Participating laboratories in the collaborative study received training in the conduct and scoring of the behavioral tests and each laboratory received a video training film to train additional personnel as needed. Each of the eight laboratories that chose to participate in the study completed proficiency testing and assessed seven representative chemicals using a functional observational battery and automated motor activity assessment. The seven chemicals studied were acrylamide, bis-acrylamide, p,p'-DDT, lead acetate, parathion, toluene, and triethyl tin. Participants received coded samples of the chemicals from a common source. Each laboratory derived doses for single and repeated administration based on the determination of a within-laboratory acute "top dose." Animal strains were not standardized and laboratory conditions were standardized to a limited degree in order to judge the general utility and robustness of these procedures in a diversity of testing situations.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: III. Results of proficiency studies. Steering Group.

The goal of the IPCS Collaborative Study on Neurobehavioral Screening Methods was to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories world-wide. The first phase of the Collaborative Study involved training the participants: evidence of training was then evaluated using positive-control compounds. The positive-control studies required the laboratories to identify, using the FOB, specific neurotoxic syndromes produced by acute exposure to p,p'-DDT, parathion, and by short-term repeated dosing with acrylamide. For the sake of expediency, only one dose of each chemical was used instead of collecting dose-response data. Motor activity test chambers were not of uniform design. The laboratories were therefore required to demonstrate adequate sensitivity by the ability to detect statistically-significant activity increases and decreases produced by triadimefon and chlorpromazine, respectively, following acute administration of a range of doses. The resulting FOB and motor activity data showed variability in the magnitude of effects obtained: some of these differences were attributed to miscommunications, difficulties with the techniques or protocol, or the limitations of having only one dose. All laboratories, however, successfully met the criteria set forth by the Study Steering Committee.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: IV. Control data. Steering Group.

The goal of the International Programme on Chemical Safety (IPCS) Collaborative Study on Neurobehavioral Screening Methods was to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories worldwide. The control data were crucial to the outcome of the studies in terms of sensitivity and reliability of the test measures, which in turn impact on the between-laboratory comparisons of chemical effects. In addition, analyses of control data can aid in determining endpoints that may require modification to improve their sensitivity and reliability. The control data from the eight laboratories were examined in terms of the following parameters: 1) control variability within studies for each laboratory; 2) within-laboratory replicability of control values across studies; 3) within-laboratory stability of control values over the course of testing for a given study; and 4) between-laboratory comparisons of parameters (1), (2), and (3). The analyses indicated considerable differences across endpoints, wherein some measures showed high variability and little replicability, while others were extremely reproducible. Generally, there were similar ranges of variability and replicability of control data across laboratories, although in some cases one or two laboratories were markedly different from the others. The physiological (weight, body temperature) and neuromuscular (grip strength, landing foot splay) endpoints exhibited the least variability, whereas the subjective assessments of reactivity varied the most. These data indicate a reasonable degree of comparability in the data generated in the participating laboratories.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: V. Results of chemical testing. Steering Group.

The IPCS Collaborative Study on Neurobehavioral Screening Methods was undertaken to determine the intra- and inter-laboratory reliability of a functional observational battery (FOB) and an automated assessment of motor activity in eight laboratories world-wide. Following the training phase and the conduct of proficiency studies in all laboratories, participants proceeded to test the effects of seven chemicals in both single dose and four-week repeated dosing scenarios. The chemicals studied were acrylamide, bisacrylamide, p,p'-DDT, lead acetate, parathion, toluene, and triethyl tin. Participants received coded samples from a common source. In order to judge the general utility of these procedures in a diversity of testing situations, laboratories conducted the studies under their standard conditions, using their choice of rat strain and test equipment. Chemical does and time of peak effect for acute testing were determined by each laboratory: these parameters were quite similar for some chemicals, but varied greatly for others. The results of the chemical tests indicated that while there was some variability in the data on specific endpoints, all laboratories detected and characterized the effects of all but one of the known neurotoxicants. The one exception (toluene) was probably due to other factors (e.g., dose level, route of administration) rather than lack of sensitivity of the test methods. This study provides extensive data regarding the use of neurobehavioral screening methods over a range of laboratory conditions as well as the reliability, sensitivity, and robustness of the tests to detect neurotoxic potential of chemicals.

Animals↗
PubMed1997

The IPCS Collaborative Study on Neurobehavioral Screening Methods: VII. Summary and conclusions.

In the International Programme on Chemical Safety (IPCS) Collaborative Study on Neurobehavioral Screening Methods, eight participating laboratories used a standard battery of behavioral tests to determine, in rats, the effects of seven representative chemicals following acute and repeated dosing. The results of the collaborative study indicate good agreement across laboratories with regard to the data collected in vehicle controls. It was clear, however, that some behavioral measures had significantly more variability than other tests. The laboratories also demonstrated the ability to detect known neurotoxic chemicals and identify profiles of effects that differed from non-neurotoxic agents. The results of the study suggest that appropriate training of personnel is crucial to ensure the reliability of the test battery. The results also underscore the importance of dose selection in behavioral screening studies, since it is sometimes difficult to determine the specificity of behavioral changes in animals receiving high doses of some chemicals. The collaborative study also emphasizes the need to utilize a battery of tests in screening a wide range of potential neurotoxic agents. Analysis of data from such studies poses unique challenges due to the large number of tests and test times, and the consequent possibility of false positives. Some statistical concerns may be alleviated by grouping the results from tests that measure similar functions into neurobiological domains. Although this approach improves confidence in the biological relevance of chemical-induced changes in behavior, it may also lead to false negatives. The exploration of other statistical approaches to analyze data from experiments using a test battery is encouraged. Nevertheless, results of the collaborative study strongly support the use of behavioral tests in hazard identification.

Animals↗
PubMed1996

Increased [3H]phorbol ester binding in rat cerebellar granule cells and inhibition of 45Ca2+ sequestration in rat cerebellum by polychlorinated diphenyl ether congeners and analogs: structure-activity relationships.

Our previous reports indicate that ortho-substituted non-coplanar polychlorinated biphenyl (PCB) congeners perturbed neuronal Ca2+-homeostasis in vitro, altered agonist-stimulated inositol phosphate accumulation, and caused protein kinase C (PKC) translocation. The structure-activity relationship (SAR) with 24 PCB congeners was consistent with a chlorination pattern that favored non-coplanarity while those with chlorination that favored coplanarity were less active. To test the hypothesis that coplanarity (or lack thereof) is a significant factor in the activity of PCBs, studies with related classes of chemicals such as the polychlorinated diphenyl ethers (PCDEs), in which coplanarity is more difficult to achieve regardless of degree and pattern of chlorination, were initiated. The selected PCDEs and their analogs are predicted to be active, since they are non-coplanar in nature. The effects of these chemicals were studied using the same measures for which PCBs had differential effects based on structural configuration. These measures include PKC translocation as determined by [3H]-phorbol ester ([3H]PDBu) binding in cerebellar granule cells and 45Ca2+ sequestration as determined by 45Ca2+ uptake by microsomes and mitochondria isolated from adult rat cerebellum. All the PCDE congeners studied, increased [3H]PDBu binding in a concentration-dependent manner. The order of potency was 2,4,4'-trichlorodiphenyl ether > 4,4'-dichlorodiphenyl ether > diphenyl ether, 3,3',4,4'-tetrachlorodiphenyl ether and, 2,2',4,4',5- and 2,3',4,4',5-pentachlorodiphenyl ethers. The structurally related diphenyl ether nitrofen and diphenyl ethanes o,p'-1,1,1-trichloro-2,2-bis[p-chlorophenyl]ethane (DDT) and p,p'-DDT increased [3H]PDBu binding to a similar extent (28-35% stimulation at 100 microM). All PCDE congeners and their analogs inhibited 45Ca2+ sequestration by microsomes and mitochondria. Of all the chemicals, unchlorinated diphenyl ether was the least active. These results are in agreement with previous SAR findings in which non-coplanar PCBs are active and support our hypothesis that the extent of coplanarity determined by a pattern of chlorination on certain aromatic hydrocarbons can weaken their potency in vitro, although the extent of chlorination is also important.

Animals↗
PubMed1996

The impact of dose rate on the neurotoxicity of acrylamide: the interaction of administered dose, target tissue concentrations, tissue damage, and functional effects.

Health agencies are often required to predict the effects of long term low level exposure in humans based on annual data involving short-term high-level exposures. Uncertainties in extrapolation can be, in part, based on potentially different mechanism associated with different exposure scenarios. This study evaluated the adequacy of short-term exposures to acrylamide for predicting neurotoxicity produced by long-term exposures. The neurotoxic effects of acrylamide (ip) were assessed in rats after acute (0-150 mg/kg), 10-day (0-30 mg/kg), 30-day (0-20 mg/kg), and 90-day (0-10 mg/kg) exposures. Behavioral endpoints included motor activity, grip strength, and the acoustic startle response. Histological examination of sciatic nerve and spinal cord was also performed. Internal and target tissue doses were estimated by measurement of the concentration of acrylamide in serum and sciatic nerve. Functional and pathological results demonstrated that the effects of acrylamide depended on the dose rate and that the neurotoxicity of acrylamide was less than that predicted by a strict dose x time relationship. Behavioral endpoints showed both qualitative and quantitative changes as a function of dose rate. Recovery of behavioral function in these studies was independent of the duration of dosing. Because duration of dosing had no impact on the kinetics of acrylamide, these data indicate that the toxicity of acrylamide is not due to an accumulation of acrylamide in the target tissue. The less than strict cumulative toxicity of acrylamide may result from an interaction between administered dose, tissue damage, and repair processes.

Acrylamide↗
PubMed1996

Disruption of inositol phosphate accumulation in cerebellar granule cells by polychlorinated biphenyls: a consequence of altered Ca2+ homeostasis.

The present study examined the activation of protein kinase C (PKC) and disruption of Ca2+ homeostasis as potential mechanisms underlying effects of the polychlorinated biphenyl (PCB) congener 2,2'-dichlorobiphenyl (DCB) on inositol phosphate (IP) signaling in cerebellar granule cells. DCB (100 microM) increased basal IP accumulation in cerebellar granule cells when the extracellular free Ca2+ concentration ([Ca2+]e) was 0.75 mM but not when [Ca2+]e was 1 microM. Ionomycin (0.1 to 30 microM), a Ca2+ ionophore, also increased basal IP accumulation and [Ca2+]i in a concentration-dependent manner in cerebellar granule cells in the absence of DCB; increases in basal IP accumulation induced by 100 microM DCB were not additive with ionomycin. Ionomycin also disrupted carbachol (CARB, 1 mM)-stimulated IP accumulation. A 30-min preincubation with 0.3 or 1.0 microM ionomycin decreased CARB-stimulated IP accumulation, whereas simultaneous addition of 1.0 and 10 microM ionomycin with CARB increased and decreased, respectively, IP accumulation. DCB caused concentration-dependent increases in intracellular free Ca2+ concentration ([Ca2+]i) in cerebellar granule cells under experimental conditions identical to those used to measure IP accumulation. Following a one-half hour exposure to DMSO, 50 or 100 microM DCB, the [Ca2+]i was 36, 103, and 453 nM, respectively. We examined whether direct or indirect activation of PKC underlies DCB-induced inhibition of agonist-stimulated IP accumulation. DCB (100 microM) did not alter PKC activity in cytosolic or membrane fractions of granule cell homogenates. In intact cells, 50 nM phorbol 12-myristate, 13-acetate (PMA) inhibited CARB-stimulated IP accumulation by 80%, an effect which was blocked completely by the PKC inhibitor bisindolylmaleimide (2 microM; BIM). However, inhibition of CARB-stimulated IP accumulation (90%) induced by 100 microM DCB was not relieved by BIM. These results suggest that (1) perturbations of Ca2+ homeostasis may underlie DCB effects on IP accumulation, (2) at a time which corresponds to addition of agonists in IP accumulation assays, [Ca2+]i is elevated in cerebellar granule cells exposed to DCB, and (3) activation of PKC is not a mechanism by which DCB inhibits agonist-stimulated IP accumulation.

Animals↗
PubMed1996

Inhibition of microsomal and mitochondrial Ca2+-sequestration in rat cerebellum by polychlorinated biphenyl mixtures and congeners. Structure-activity relationships.

Recent studies from our laboratory indicate that polychlorinated biphenyl (PCB) congeners in vitro perturbed signal transduction mechanisms including cellular Ca2+-homeostasis and protein kinase C translocation. We have now investigated the structure-activity relationship (SAR) of three PCB mixtures, 24 PCB congeners and one dibenzofuran for their effects on microsomal and mitochondrial Ca2+-sequestration in rat cerebellum. Ca2+-sequestration by these intracellular organelles was determined using radioactive 45CaCl2. All three mixtures studied, Aroclor 1016, Aroclor 1254 and Aroclor 1260, were equally potent in inhibiting microsomal and mitochondrial Ca2+-sequestration with IC50 values of 6-8 microM. 1,2,3,7,8-Pentachlorodibenzofuran had no effect on Ca2+-sequestration by these organelles. The SAR among the congeners revealed: (1) congeners with ortho-/meta- or ortho-, para-chlorine substitutions were the most potent in inhibiting microsomal and mitochondrial Ca2+-sequestration (IC50 = 2.4-22.3 microM); (2) congeners with only para- but without ortho-substitutions were not effective in inhibiting Ca2+-sequestration by microsomes and mitochondria; (3) increased chlorination was not related to the effectiveness of these congeners. The present SAR studies indicate that the effects of most PCB congeners in vitro may be related to an interaction at specific sites having preference for low lateral substitution or lateral content (meta- or para) in the presence of ortho-substitution.

Animals↗
PubMed1996

Setting exposure standards: a decision process.

Increased emphasis on routine screening of chemicals for potential neurotoxicity has resulted in the development of testing guidelines and standardized procedures. A multiphased, tiered-testing strategy has been proposed by numerous expert panels to evaluate large numbers of chemicals. In a regulatory context, however, a formal tiered-testing approach is not used, mostly because of the constraints of differing regulatory authorities and the potential cost of such a testing strategy. Instead, current regulatory decision making utilizes all available animal and human data to identify a critical adverse effect which is then used for setting standards. Although the current decision-making process does not use a formal tiered-testing approach, it appears to identify chemicals with neurotoxic effects. An analysis of U.S. Environmental Protection Agency integrated risk information system (IRIS) indicates that about 20% of the chemicals having standards or health advisories are based on neurotoxicity.

Algorithms↗
PubMed1996

Research needs for the risk assessment of health and environmental effects of endocrine disruptors: a report of the U.S. EPA-sponsored workshop.

The hypothesis has been put forward that humans and wildlife species adverse suffered adverse health effects after exposure to endocrine-disrupting chemicals. Reported adverse effects include declines in populations, increases in cancers, and reduced reproductive function. The U.S. Environmental Protection Agency sponsored a workshop in April 1995 to bring together interested parties in an effort to identify research gaps related to this hypothesis and to establish priorities for future research activities. Approximately 90 invited participants were organized into work groups developed around the principal reported health effects-carcinogenesis, reproductive toxicity, neurotoxicity, and immunotoxicity-as well as along the risk assessment paradigm-hazard identification, dose-response assessment, exposure assessment, and risk characterization. Attention focused on both ecological and human health effects. In general, group felt that the hypothesis warranted a concerted research effort to evaluate its validity and that research should focus primarily on effects on development of reproductive capability, on improved exposure assessment, and on the effects of mixtures. This report summarizes the discussions of the work groups and details the recommendations for additional research.

Animals↗
PubMed1995

Increased [3H]phorbol ester binding in rat cerebellar granule cells by polychlorinated biphenyl mixtures and congeners: structure-activity relationships.

Our previous reports indicate that polychlorinated biphenyl (PCB) congeners in vitro perturbed cellular Ca2+ homeostasis and protein kinase C (PKC) translocation. We have now studied the structure-activity relationship (SAR) of 3 PCB mixtures, 24 PCB congeners, and 1 dibenzofuran for their effects on PKC translocation by measuring [3H]phorbol ester ([3H]PDBu) binding in cerebellar granule cells (7 days in culture). All the PCB mixtures studied increased [3H]PDBu binding significantly and in a concentration-dependent manner. However, Aroclor 1016 and Aroclor 1254 were more potent than Aroclor 1260. Of the 24 congeners studied, di-ortho congeners such as 2,2',5,5'-tetrachlorobiphenyl (-TeCB), 2,2',4,6,6'-pentachlorobiphenyl (-PeCB), 2,2',4,6-TeCB, and 2,2'-dichlorobiphenyl (-DCB) were the most potent (E50 = 28-43 microM) while non-ortho congeners such as 3,3',4,4'-TeCB and 3,3',4,4'5-PeCB were not effective. The potential contaminant of PCB mixtures, 1,2,3,7,8-pentachlorodibenzofuran had no significant effect on [3H]PDBu binding. The SAR among these congeners revealed: (i) congeners with ortho-chlorine substitution such as 2,2'-DCB (EC50 = 43 +/- 3 microM) or ortho-lateral (meta, para) chlorine substitution such as 2,2',5,5'-TeCB (EC50 = 28 +/- 3 microM) and 2,2'4,6-TeCB (E50 = 41 +/- 6 microM) were most potent; (ii) congeners with only para-substitution such as 4,4'-DCB or high lateral content in the absence of ortho-substitution such as 3,3',4,4',5,5'-HCB were not effective; and (iii) increased chlorination was not clearly related to the effectiveness of these congeners, although hexa- and heptachlorination was less effective than di- and tetrachlorination. Low lateral substitution, especially without para-substitution, or lateral content in the presence of ortho-substitution, may be the most important structural requirement for the in vitro activity of these PCB congeners in neuronal preparations.

Analysis of Variance↗
PubMed1995

Trimethyltin increases interleukin (IL)-1 alpha, IL-6 and tumor necrosis factor alpha mRNA levels in rat hippocampus.

Within the central nervous system (CNS), cytokines are though to have active roles in pathophysiological changes seen in various neurological diseases and trauma. The present study was undertaken to examine the early response of pro-inflammatory cytokines following exposure to a specific neurotoxicant (trimethyltin; TMT). mRNA levels for interleukin (IL)-1 alpha, IL-1 beta, IL-6 and tumor necrosis factor (TNF) alpha were measured in the hippocampus of adult male Long-Evans hooded rats following an acute injection of trimethyltin hydroxide (8 mg TMT/kg body weight). At various times following exposure (6 h to 8 days), hippocampal tissues were excised and relative changes in cytokine mRNA levels were assessed by reverse transcription and polymerase chain reaction. IL-1 alpha, IL-6 and TNF alpha mRNA levels in the hippocampus increased within 6 h and remained elevated for 8 days. Quantitative analysis of mRNA transcripts revealed a two-fold increase in both IL-6 and TNF alpha within 6 h and a continued elevation of TNF alpha to 9-fold by 12 h. Within 96 h, glial fibrillary acidic protein (GFAP) mRNA levels were elevated in the hippocampus. Histological examination showed sparse individual neuronal necrosis at this time in both the pyramidal and granule cell regions with no increase in astrocyte GFAP immunoreactivity. However, an early, 24 h, response of microglial cells was indicated by increased lectin binding. This morphological profile progressed over time to a profound neuronal loss in the CA3-4 granule cell layer and marked astrocyte hypertrophy. The onset of pro-inflammatory cytokine mRNA expression appears to be temporally associated with histological evidence of elevated microglia in the hippocampus. It is proposed that microglia and pro-inflammatory cytokines play a modulatory role in the early stages of TMT-induced neurotoxicity.

Animals↗
PubMed1995

The concern for developmental neurotoxicology: is it justified and what is being done about it?

In general, it is believed that the possibility of an adverse developmental outcome following conception is relatively high. In most cases, the cause of the defect is not clear, although exposure to chemical agents at a critical period during development has been proposed to play a significant role. Consequently, regulatory agencies such as the U.S. Environmental Protection Agency (U.S. EPA) have promulgated testing guidelines for assessing developmental neurotoxicity of chemicals in animal testing protocols. Concerns have been expressed about the use of behavioral tests to evaluate chemicals for developmental neurotoxicity, since some investigators believe that they lack predictive validity for human developmental neurotoxicity. Other investigators have indicated that results from such studies are difficult to interpret because of a lack of standardization and sensitivity of the tests. Furthermore, it has been argued that the developing organism is not especially sensitive to chemicals or, if effects are observed, the developing organism is capable of compensating for the deficit. Recent research, however, has adequately demonstrated that developing organisms are especially vulnerable to chemical agents if the exposure occurs at a critical period during development, while other studies have supported the assumption that functional or behavioral effects observed in animal models can be extrapolated to humans. These findings support the routine assessment of chemicals for developmental neurotoxicity using functional end points and suggest that currently available methods could be used to determine more precisely the mechanism of chemical-induced developmental defects.

Animals↗
PubMed1995

Defining neurotoxicity in a decision-making context.

Neurotoxicity is one of several noncancer endpoints used by regulatory agencies in risk assessment. At the US EPA, neurotoxicity is defined as an adverse change in the structure and/or function of the central and/or peripheral nervous system measured at the neurochemical, behavioral, neurophysiological or anatomical levels. Adverse effects include alterations that diminish an organism's ability to survive, reproduce or adapt to the environment. Generally, a weight-of-evidence approach is used to evaluate observed effects. There is, for example, a high level of concern for persistent changes in the function or structure of the nervous system, while transient changes must be evaluated using further criteria. Compensatory changes resulting from cell death might represent activation of repair capacity and, since this could decrease future potential adaptability, reversibility is viewed with concern. In general, equal weight is given to chemicals that directly or indirectly affect the nervous system. Finally, effects on the nervous system must be compared to those on other organ systems to help rule out non-specific changes in neurobiological measures.

Animals↗