Neurobehavioral Endpoints Research Articles

Multilevel meta-analysis and dose-response analysis for bisphenol A (BPA) exposure on metabolic and neurobehavioral effects

Evidence suggests that oral exposure to bisphenol A (BPA) may result in adverse metabolic and neurobehavioral effects. The aim of the present meta-analysis is to examine this association based on systematically selected laboratory rodent studies published from 2012 to 2021 and sourced from Scopus, Web of Science, EmBase, and PubMed. Articles satisfying eligibility and inclusion criteria were included for the calculation of the summary standardised mean difference (SMD). Subgroup analysis and subsequent dose-response analysis were conducted if applicable. In total, 32 studies were analysed for 6 metabolic endpoints (cholesterol, triglycerides, insulin, glucose, leptin, and adiponectin) and 6 neurobehavioral endpoints (locomotor activity, exploratory, anxiety, depression, spatial learning and memory, non-spatial learning and memory). Summary SMDs implied that no significant effects were observed in endpoints considered. The dose was not determined as a significant moderator with regards to medium or high heterogeneity; however, there was significant impairment of spatial learning and memory at health-based guidance value (‘HBGV’) (0.05–9 mg (kg bw)−1 day−1) and ‘High’ (>9 mg (kg bw)−1 day−1) dose group. As a result, an indicative toxicological reference dose value of 0.034 mg (kg bw)−1 day−1 was proposed due to large variability. Potential harm to spatial learning and memory from BPA exposure requires further investigation. This study has provided some additional information on potential adverse metabolic and neurobehavioral effects of BPA from the perspective of meta-analysis which can inform the public, regulatory authorities, and policymakers.

Neurotoxicity of tetramethylammonium ion on larval and juvenile zebrafish: Effects on neurobehaviors and multiple biomarkers

Tetramethylammonium hydroxide (TMAH) is an important compound that utilized and released by the rapidly expanding semiconductor industry, which could hardly be removed by the conventional wastewater treatment techniques. As a cholinergic agonist, the tetramethylammonium ion (TMA+) has been reported to induce toxicity to muscular and respiratory systems of mammals and human, however the toxicity on aquatic biota remains poorly known. We investigated the neurotoxic effects of TMA+ exposure on zebrafish, based on neurobehavior tests and a series of biomarkers. Significant inhibitions on the swimming distance of zebrafish larvae were observed when the exposure level exceeded 50 mg/L, and significant alterations on swimming path angles (straight and deflective movements) occurred even at 10 mg/L. The tested neurobehavioral endpoints of zebrafish larvae were significantly positively correlated with reactive oxygen species (ROS) and malondialdehyde (MDA), significantly negatively related with the activities of antioxidant enzymes, but not significantly correlated with the level of acetylcholinesterase (AChE). Such relationship indicates that the observed neurotoxic effects on swimming behavior of zebrafish larvae is mainly driven by oxidative stress, rather than the alterations of neurotransmitter. At the highest exposure concentration (200 mg/L), TMA+ evoked more severe toxicity on zebrafish juveniles, showing significantly stronger elevation on the MDA activity, and greater inhibitions on the activities of antioxidant enzymes and AChE, suggesting juveniles were more susceptible to TMA+ exposure than larval zebrafish.

Effects of Ozone on Sickness and Depressive-like Behavioral and Biochemical Phenotypes and Their Regulation by Serum Amyloid A in Mice.

Ozone (O3) is an air pollutant that primarily damages the lungs, but growing evidence supports the idea that O3 also harms the brain; acute exposure to O3 has been linked to central nervous system (CNS) symptoms such as depressed mood and sickness behaviors. However, the mechanisms by which O3 inhalation causes neurobehavioral changes are limited. One hypothesis is that factors in the circulation bridge communication between the lungs and brain following O3 exposure. In this study, our goals were to characterize neurobehavioral endpoints of O3 exposure as they relate to markers of systemic and pulmonary inflammation, with a particular focus on serum amyloid A (SAA) and kynurenine as candidate mediators of O3 behavioral effects. We evaluated O3-induced dose-, time- and sex-dependent changes in pulmonary inflammation, circulating SAA and kynurenine and its metabolic enzymes, and sickness and depressive-like behaviors in Balb/c and CD-1 mice. We found that 3 parts per million (ppm) O3, but not 2 or 1 ppm O3, increased circulating SAA and lung inflammation, which were resolved by 48 h and was worse in females. We also found that indoleamine 2,3-dioxygenase (Ido1) mRNA expression was increased in the brain and spleen 24 h after 3 ppm O3 and that kynurenine was increased in blood. Sickness and depressive-like behaviors were observed at all O3 doses (1-3 ppm), suggesting that behavioral responses to O3 can occur independently of increased SAA or neutrophils in the lungs. Using SAA knockout mice, we found that SAA did not contribute to O3-induced pulmonary damage or inflammation, systemic increases in kynurenine post-O3, or depressive-like behavior but did contribute to weight loss. Together, these findings indicate that acute O3 exposure induces transient symptoms of sickness and depressive-like behaviors that may occur in the presence or absence of overt pulmonary neutrophilia and systemic increases of SAA. SAA does not appear to contribute to pulmonary inflammation induced by O3, although it may contribute to other aspects of sickness behavior, as reflected by a modest effect on weight loss.

Trans-generational effects of copper on nerve damage in Caenorhabditis elegans

The potential toxicity of copper has received great attention for a long time, however, trans-generational effects of copper have not been extensively investigated. Caenorhabditis elegans (C. elegans) was used to evaluate the trans-generational toxicities of copper several physiological endpoints: growth, head thrashes and body bends and degree of neuronal damage. Copper significantly inhibited growth, body bends, head thrashes and caused degeneration of dopaminergic neurons in a concentration-dependent manner in parental worms. Further we found oxidative damage was to underlying the onset of neuron degeneration. In our study copper promoted ROS accumulation, and led to an increased expression of the oxidative stress response-related genes sod-3 and a decreased expression of metal detoxification genes mtl-1 and mtl-2. Moreover, copper increased the fluorescence intensity of the transgenic strain that encodes the antioxidant enzyme SOD-3. Gradually decline in copper-induced impairments were observed in the filial generations without exposure. No growth impairment was shown in F3, the trend of head thrashes recovery gradually appeared in F2 and no growth impairment was shown in F3, the body bends impairment caused by the parental copper exposure was recovery until F4 and no growth impairment was shown in F5. Besides, dopamine neurons revealed damage related to neurobehavioral endpoints, with hereditary effects in the progeny together. In addition, sequencing results suggested that copper exposure could cause epigenetic changes. QRT-PCR results showed that differentially expressed genes can also be passed on to offspring.

Determinants of suboptimal CD4+ T cell recovery after antiretroviral therapy initiation in a prospective cohort of acute HIV‐1 infection

IntroductionUp to 30% of individuals treated with antiretroviral therapy (ART) during chronic HIV fail to recover CD4 counts to >500 cells/mm3 despite plasma viral suppression. We investigated the frequency and associations of suboptimal CD4 recovery after ART started during acute HIV infection (AHI).MethodsParticipants who started ART in Fiebig I to V AHI with ≥48 weeks of continuous documented HIV‐RNA < 50 copies/mL were stratified by CD4 count at latest study visit to suboptimal immune recovery (SIR; CD4 < 350 cells/mm3), intermediate immune recovery (IIR; 350 ≤ CD4 < 500) and complete immune recovery (CIR; CD4 ≥ 500). Clinical and laboratory parameters were assessed at pre‐ART baseline and latest study visit. Additional inflammatory and neurobehavioral endpoints were examined at baseline and 96 weeks.ResultsOf 304 participants (96% male, median 26 years old) evaluated after median 144 (range 60 to 420) weeks of ART initiated at median 19 days (range 1 to 62) post‐exposure, 3.6% (n = 11) had SIR and 14.5% (n = 44) had IIR. Pre‐ART CD4 count in SIR compared to CIR participants was 265 versus 411 cells/mm3 (p = 0.002). Individuals with SIR or IIR had a slower CD4 rate of recovery compared to those with CIR. Timing of ART initiation by Fiebig stage did not affect CD4 count during treatment. Following ART, the CD8+T cell count (p = 0.001) and CD4/CD8 ratio (p = 0.047) were lower in SIR compared to CIR participants. Compared to the CIR group at week 96, the combined SIR and IIR groups had higher sCD14 (p = 0.008) and lower IL‐6 (p = 0.04) in plasma, without differences in neuropsychological or psychiatric indices.ConclusionsDespite immediate and sustained treatment in AHI, suboptimal CD4 recovery occurs uncommonly and is associated with low pre‐ART CD4 count as well as persistent low CD8 count and CD4/CD8 ratio during treatment.

Trans-generational effect of neurotoxicity and related stress response in Caenorhabditis elegans exposed to tetrabromobisphenol A

Tetrabromobisphenol A (TBBPA), one of the most common brominated flame retardants, has been associated with immunotoxicity, neurotoxicity, and reproductive toxicity. However, little attention has been focused on understanding the trans-generational effects of TBBPA. The present study used the Caenorhabditis elegans (C. elegans) animal model to evaluate the trans-generational effects of neurotoxicity induced by environmentally relevant concentrations of TBBPA (0, 0.1, 1, 10, 100, and 1000 µg/L). Multiple indicators including physiological effects (body length, brood size, head thrashes, body bends, and crawling trajectory), degree of neuronal damage (dopamine, GABAergic, and glutamatergic neurons), oxidative stress-related biochemical indicators (superoxide dismutase [SOD] activity, catalase [CAT] enzyme, malondialdehyde [MDA] production, and reactive oxygen species [ROS] accumulation), and stress-related gene expressions have been evaluated in the exposed parental C. elegans generation (G1) and their progeny (G2) under TBBPA-free conditions. The results showed that TBBPA exposure induced adverse effects on physiological endpoints, among which body bends and head thrashes were the most sensitive ones, detected above 1 µg/L in G1 and 100 µg/L in G2 nematodes, respectively. After contaminant exposure, the three neurons revealed damage related to neurobehavioral endpoints, with no hereditary effects in the progeny. The oxidative stress-related biochemical endpoints demonstrated that when the exposure concentrations were above 1 µg/L in maternal worms, impairment can be detected in both generations, but the progeny recovered at low toxicity concentration (1–100 µg/L). The integrated target gene expression profiles were clearly altered in G1 and G2 worms at concentrations between 1 and 1000 µg/L, and a more significant difference existed in two generations of nematodes at low levels (1–10 µg/L) of TBBPA. Studing trans-generational neurotoxicity and the underlying mechanism can generate a precise evaluation of the environmental risk of TBBPA.

Impact of digital video analytics on accuracy of chemobehavioural phenotyping in aquatic toxicology.

Chemobehavioural phenotypic analysis using small aquatic model organisms is becoming an important toolbox in aquatic ecotoxicology and neuroactive drug discovery. The analysis of the organisms’ behavior is usually performed by combining digital video recording with animal tracking software. This software detects the organisms in the video frames, and reconstructs their movement trajectory using image processing algorithms. In this work we investigated the impact of video file characteristics, video optimization techniques and differences in animal tracking algorithms on the accuracy of quantitative neurobehavioural endpoints. We employed larval stages of a free-swimming euryhaline crustacean Artemia franciscana,commonly used for marine ecotoxicity testing, as a proxy modelto assess the effects of video analytics on quantitative behavioural parameters. We evaluated parameters such as data processing speed, tracking precision, capability to perform high-throughput batch processing of video files. Using a model toxicant the software algorithms were also finally benchmarked against one another. Our data indicates that variability in video file parameters; such as resolution, frame rate, file containers types, codecs and compression levels, can be a source of experimental biases in behavioural analysis. Similarly, the variability in data outputs between different tracking algorithms should be taken into account when designing standardized behavioral experiments and conducting chemobehavioural phenotyping.

Chronic, low-level oral exposure to marine toxin, domoic acid, alters whole brain morphometry in nonhuman primates

Domoic acid (DA) is an excitatory neurotoxin produced by marine algae and responsible for Amnesiac Shellfish Poisoning in humans. Current regulatory limits (˜0.075-0.1 mg/kg/day) protect against acute toxicity, but recent studies suggest that the chronic consumption of DA below the regulatory limit may produce subtle neurotoxicity in adults, including decrements in memory. As DA-algal blooms are increasing in both severity and frequency, we sought to better understand the effects of chronic DA exposure on reproductive and neurobehavioral endpoints in a preclinical nonhuman primate model. To this end, we initiated a long-term study using adult, female Macaca fascicularis monkeys exposed to daily, oral doses of 0.075 or 0.15 mg/kg of DA for a range of 321–381, and 346–554 days, respectively. This time period included a pre-pregnancy, pregnancy, and postpartum period. Throughout these times, trained data collectors observed intentional tremors in some exposed animals during biweekly clinical examinations. The present study explores the basis of this neurobehavioral finding with in vivo imaging techniques, including diffusion tensor magnetic resonance imaging and spectroscopy. Diffusion tensor analyses revealed that, while DA exposed macaques did not significantly differ from controls, increases in DA-related tremors were negatively correlated with fractional anisotropy, a measure of structural integrity, in the internal capsule, fornix, pons, and corpus callosum. Brain concentrations of lactate, a neurochemical closely linked with astrocytes, were also weakly, but positively associated with tremors. These findings are the first documented results suggesting that chronic oral exposure to DA at concentrations near the current human regulatory limit are related to structural and chemical changes in the adult primate brain.

Transient exposure of methylparaben to zebrafish (Danio rerio) embryos altered cortisol level, acetylcholinesterase activity and induced anxiety-like behaviour

Parabens are widely used as antimicrobial preservatives. Recent studies have reported the endocrine disrupting effects of these chemicals, especially methylparaben. Previously, we have reported the alteration in Vtg gene expression upon exposure to environmentally relevant doses of methylparaben in zebrafish (Danio rerio) embryos. However, studies reporting neurobehavioural outcomes on exposure to methylparaben are limited. Therefore, this study was aimed at investigating the methylparaben-induced effects on developmental and neurobehavioural endpoints. Zebrafish embryos were exposed to sub-lethal concentrations of methylparaben: 0.1 ppb, 1 ppb, 10 ppb and 100 ppb. Alterations in developmental landmarks such as heart rate and hatching percentage were observed in embryos exposed to 10 ppb and 100 ppb of methylparaben. Results obtained from the novel tank diving test established that anxiety-like behaviour is induced in larvae exposed to 0.1 ppb and 1 ppb of methylparaben. A significant inhibition in the acetylcholinesterase (AChE) activity was also recorded in methylparaben-exposed groups. An increase in cortisol levels was observed in the exposed groups, which further supports the observations made in the novel tank diving test, establishing methylparaben as an anxiogenic agent even at sub-lethal concentrations. The underlying molecular mechanism needs further elucidation to investigate whether the behavioural effects are proximally or distally induced by early developmental exposure to methylparaben.

Nonclinical Safety Assessment of CFZ533, a Fc-Silent Anti-CD40 Antibody, in Cynomolgus Monkeys.

CFZ533 is a pathway blocking, nondepleting anti-CD40 antibody that is in clinical development for inhibition of transplant organ rejection and therapy for autoimmune diseases. A 26-week GLP toxicity study in sexually mature Cynomolgus monkeys was conducted in order to support chronic application of CFZ533. CFZ533 was subcutaneously administered at doses up to 150 mg/kg/week and was safe and generally well tolerated. CFZ533 showed no adverse effects for cardiovascular, respiratory, and neurobehavioral endpoints, and no changes were observed for blood lymphocyte and platelet counts or blood coagulation markers. In line with the nondepleting nature of CFZ533, CD20+ B cells in the blood were only marginally reduced. A complete suppression of germinal center (GC) development in lymph nodes and spleen was the most prominent result of post-mortem histological investigations. This was corroborated by an abrogated T-dependent antibody response (TDAR) to the antigen Keyhole Limpet Hemocyanin (KLH) as well as an absence of anti-drug antibodies (ADAs) in the absence of B cell depletion as seen with immunophenotyping and histology. When serum levels of CFZ533 in recovery animals dropped levels necessary for full CD40 occupancy on B cells, all animals were able to mount a TDAR to KLH. All histological changes also reverted to normal appearance after recovery. In summary, CFZ533 was shown to be well tolerated and safe in the 26-week toxicity study with a distinct pharmacodynamic profile in histology and immune function.

Multidimensional chemobehavior analysis of flavonoids and neuroactive compounds in zebrafish

The comparative analysis of complex behavioral phenotypes is valuable as a reductionist tool for both drug discovery and defining chemical bioactivity. Flavonoids are a diverse class of chemicals that elicit robust neuroactive and hormonal actions, though bioactivity information is limited for many, particularly for neurobehavioral endpoints. Here, we used a zebrafish larval chemomotor response (LCR) bioassay to comparatively evaluate a suite of 24 flavonoids, and in addition a panel of 30 model neuroactive compounds representing diverse modes of action (e.g. caffeine, chlorpyrifos, methamphetamine, nicotine, picrotoxin). Naïve larval zebrafish were exposed to concentration ranges of each compound at 120 hour post-fertilization (hpf) and locomotor activity measured for 5 h. The model neuroactive compounds were largely behaviorally bioactive (20 of 30) with most effects phenotypic of their known modes of action. Flavonoids rapidly and broadly elicited hyperactive locomotor effects (22 of 24). Multidimensional analyses compared responses over time and identified three distinct bioactive groups of flavonoids based on efficacy and potency. Using GABAergics to modulate hyperactive responses, two flavonoids, (S)-equol and kaempferol were tested for GABAA receptor antagonism, as well as a known GABAA receptor antagonist, picrotoxin. Pharmacological intervention with positive allosteric modulators of the GABAA receptor, alfaxalone and chlormethiazole, ameliorated the hyperactive response to picrotoxin, but not for (S)-equol or kaempferol. Taken together, these studies demonstrate that flavonoids are differentially bioactive and that the chemobehavioral effects likely do not involve a GABAA receptor mediated mode of action. Overall, the integrative zebrafish platform provides a useful framework for comparatively evaluating high-content chemobehavioral data for sets of structurally- and mechanistically-related flavonoids and neuroactive compounds.

Minimal Long-Term Neurobehavioral Impairments after Endovascular Perforation Subarachnoid Hemorrhage in Mice

Cognitive deficits are among the most severe and pervasive consequences of aneurysmal subarachnoid hemorrhage (SAH). A critical step in developing therapies targeting such outcomes is the characterization of experimentally-tractable pre-clinical models that exhibit multi-domain neurobehavioral deficits similar to those afflicting humans. We therefore searched for neurobehavioral abnormalities following endovascular perforation induction of SAH in mice, a heavily-utilized model. We instituted a functional screen to manage variability in injury severity, then assessed acute functional deficits, as well as activity, anxiety-related behavior, learning and memory, socialization, and depressive-like behavior at sub-acute and chronic time points (up to 1 month post-injury). Animals in which SAH was induced exhibited reduced acute functional capacity and reduced general activity to 1 month post-injury. Tests of anxiety-related behavior including central area time in the elevated plus maze and thigmotaxis in the open field test revealed increased anxiety-like behavior at subacute and chronic time-points, respectively. Effect sizes for subacute and chronic neurobehavioral endpoints in other domains, however, were small. In combination with persistent variability, this led to non-significant effects of injury on all remaining neurobehavioral outcomes. These results suggest that, with the exception of anxiety-related behavior, alternate mouse models are required to effectively analyze cognitive outcomes after SAH.

Neurobehavioral endpoints in non-human primates integrated in toxicology studies

Neurobehavioral endpoints in non-human primates integrated in toxicology studies

Inclusion of neurobehavioural and respiratory safety pharmacology endpoints in the 4-week rat general toxicology studies

Inclusion of neurobehavioural and respiratory safety pharmacology endpoints in the 4-week rat general toxicology studies

Predicting the neurobehavioral side effects of dexamethasone in pediatric acute lymphoblastic leukemia

Although dexamethasone is an effective treatment for acute lymphoblastic leukemia (ALL), it can induce a variety of serious neurobehavioral side effects. We hypothesized that these side effects are influenced by glucocorticoid sensitivity at the tissue level. We therefore prospectively studied whether we could predict the occurrence of these side effects using the very low-dose dexamethasone suppression test (DST) or by measuring trough levels of dexamethasone. Fifty pediatric patients (3–16 years of age) with acute lymphoblastic leukemia (ALL) were initially included during the maintenance phase (with dexamethasone) of the Dutch ALL treatment protocol. As a marker of glucocorticoid sensitivity, the salivary very low-dose DST was used. A post-dexamethasone cortisol level <2.0nmol/L was considered a hypersensitive response. The neurobehavioral endpoints consisted of questionnaires regarding psychosocial and sleeping problems administered before and during the course of dexamethasone (6mg/m2), and dexamethasone trough levels were measured during dexamethasone treatment. Patients with a hypersensitive response to dexamethasone had more behavioral problems (N=11), sleeping problems, and/or somnolence (N=12) (P<0.05 for all three endpoints). The positive predictive values of the DST for psychosocial problems and sleeping problems were 50% and 30%, respectively. Dexamethasone levels were not associated with neurobehavioral side effects. We conclude that neither the very low-dose DST nor measuring dexamethasone trough levels can accurately predict dexamethasone-induced neurobehavioral side effects. However, patients with glucocorticoid hypersensitivity experienced significantly more symptoms associated with dexamethasone-induced depression. Future studies should elucidate further the mechanisms by which neurobehavioral side effects are influenced by glucocorticoid sensitivity.

Toxicological Evaluation of β-Caryophyllene Oil: Subchronic Toxicity in Rats.

In a subchronic toxicity study, administration of β-caryophyllene (BCP) oil by oral gavage to Wistar rats at dosages of 0, 150, 450, or 700 mg/kg/d for 90 days, including a 21-day recovery period, did not produce any significant toxicologic manifestations. The study design also included a 28-day interim sacrifice in the control and high-dose groups. The BCP oil test article was well tolerated as evidenced by the absence of major treatment-related changes in the general condition and appearance of the rats, neurobehavioral end points, growth, feed and water intake, ophthalmoscopic examinations, routine hematology and clinical chemistry parameters, urinalysis, and necropsy findings. The no observed adverse effect level was the highest dosage level administered of 700 mg/kg body weight/d for both male and female rats. The study was conducted as part of an investigation to examine the safety of BCP oil for its proposed use in medical food products.

Avian Test Battery for the Evaluation of Developmental Abnormalities of Neuro- and Reproductive Systems

Most of the currently used toxicity assays for environmental chemicals use acute or chronic systemic or reproductive toxicity endpoints rather than neurobehavioral endpoints. In addition, the current standard approaches to assess reproductive toxicity are time-consuming. Therefore, with increasing numbers of chemicals being developed with potentially harmful neurobehavioral effects in higher vertebrates, including humans, more efficient means of assessing neuro- and reproductive toxicity are required. Here we discuss the use of a Galliformes-based avian test battery in which developmental toxicity is assessed by means of a combination of chemical exposure during early embryonic development using an embryo culture system followed by analyses after hatching of sociosexual behaviors such as aggression and mating and of visual memory via filial imprinting. This Galliformes-based avian test battery shows promise as a sophisticated means not only of assessing chemical toxicity in avian species but also of assessing the risks posed to higher vertebrates, including humans, which are markedly sensitive to nervous or neuroendocrine system dysfunction.

Combining neurobehavioral and neurophysiological endpoints to dissociate evidence of tremors from seizure liability in the beagle dog

Combining neurobehavioral and neurophysiological endpoints to dissociate evidence of tremors from seizure liability in the beagle dog

Effects of prenatal exposure to single-wall carbon nanotubes on reproductive performance and neurodevelopment in mice.

Carbon nanotubes with extraordinary properties may become a novel drug and gene delivery tool in nanomedicine; however, insufficient information is available regarding their biosafety. Therefore, this work was performed to study the effect of prenatal exposure of single-walled carbon nanotubes (SWCNTs) on reproductive and neurobehavioral endpoints in mice. Thirty pregnant female mice were assigned to three groups (n = 10 for each group). The two treated groups were injected intraperitoneally (i.p.) with 1 or 10 mg/kg body weight (b.w.) of SWCNTs suspended in 1 ml of phosphate buffer saline (PBS) on gestational days 0 and 3. The control group was injected i.p. with an equal volume of PBS. The neurobehavioral ontogeny of pups was evaluated using a modified Fox battery. A decrease in litter size on postnatal day 2 was observed in the group treated with 10 mg/kg b.w. of SWCNTs whereas no significant differences between groups were observed in any other parameters. The behavioral development of pups did not show significant differences during growth except for the surface righting reflex, which showed significant delay compared to control in the group treated with 1 mg/kg b.w. SWCNTs. Moreover, exposed offspring (10 mg/kg b.w. SWCNTs) displayed enhanced anxiety in the elevated plus maze; however, other ethological analysis (Morris water maze and open field test) did not show behavioral changes in the experimental groups. In conclusion, the present results demonstrated small changes in offspring sensory and motor development following exposure to SWCNTs and support the idea that SWCNT risk assessment merits further investigation.

Inclusion of neurobehavioural and respiratory safety pharmacology endpoints in the four-week rat general toxicology studies: A CRO perspective

Inclusion of neurobehavioural and respiratory safety pharmacology endpoints in the four-week rat general toxicology studies: A CRO perspective