Caregiver placebo effect in analgesic clinical trials for cats with naturally occurring degenerative joint disease-associated pain.

A literature review identified six placebo-controlled studies of analgesics in client-owned cats with degenerative joint disease-associated pain. Five studies with 96 cats had available data. Caregiver responses on a clinical metrology instrument, Client-Specific Outcome Measure (CSOM), were compared to measured activity. Cats were categorised as 'successes' or 'failures' based on change in CSOM score and activity counts from baseline. Effect sizes based on CSOM score were calculated; factors that were associated with success/failure were analysed using logistic regression. Effect sizes ranged from 0.97 to 1.93. The caregiver placebo effect was high, with 54-74 per cent of placebo-treated cats classified as CSOM successes compared with 10-63 per cent of cats classified as successes based on objectively measured activity. 36 per cent of CSOM successes were also activity successes, while 19 per cent of CSOM failures were activity successes. No significant effects of cat age, weight, baseline activity, radiographic score, orthopaedic pain score or study type on CSOM success in the placebo groups were found. The caregiver placebo effect across these clinical trials was remarkably high, making demonstration of efficacy for an analgesic above a placebo difficult. Further work is needed to determine whether a potential placebo-by-proxy effect could benefit cats in clinical settings.

Neurological impacts from inhalation of pollutants and the nose-brain connection.

The effects of inhaled particles have focused heavily on the respiratory and cardiovascular systems. Most studies have focused on inhaled metals, whereas less information is available for other particle types regarding the effects on the brain and other extra-pulmonary organs. We review here the key available literature on nanoparticle uptake and transport through the olfactory pathway, the experimental data from animal and in vitro studies, and human epidemiological observations. Nanoparticles (<0.1 µm in one dimension) may easily reach the brain from the respiratory tract via sensory neurons and transport from the distal alveoli into the blood or lymph as free particles or inside phagocytic cells. These mechanisms and subsequent biologic responses may be influenced by the chemical composition of inhaled particles. Animal studies with ambient particulate matter and certain other particles show alterations in neuro-inflammatory markers of oxidative stress and central neurodegeneration. Human observations indicate motor, cognitive, and behavioral changes especially after particulate metal exposure in children. Exposure to co-pollutants and/or underlying disease states could also impact both the biokinetics and effects of airborne particles in the brain. Data are needed from the areas of inhalation, neurology, and metal toxicology in experimental and human studies after inhalation exposure. An increased understanding of the neurotoxicity associated with air pollution exposure is critical to protect susceptible individuals in the workplace and the general population.

Gene expression changes following acute hydrogen sulfide (H2S)-induced nasal respiratory epithelial injury.

Hydrogen sulfide (H2S) is a naturally occurring gas that is also associated with several industries. The potential for widespread human inhalation exposure to this toxic gas is a public health concern. The nasal epithelium is especially susceptible to H2S-induced pathology. Injury to and regeneration of the nasal respiratory mucosa occurred in animals with ongoing H2S exposure, suggesting that the regenerated respiratory epithelium under-goes an adaptive response and becomes resistant to further injury. To better understand this response, ten-week-old male Sprague-Dawley rats were exposed nose-only to either air or 200 ppm H2S for three hours per day for one day or five consecutive days. Nasal respiratory epithelial cells at the site of injury and regeneration were laser capture microdissected, and gene expression profiles were generated at three, six, and twenty-four hours after the initial three-hour exposure and at twenty-four hours after the fifth exposure using the Affymetrix Rat Genome 230 2.0 microarray. Gene ontology enrichment analysis showed that H2S exposure altered gene expression associated with a variety of biological processes, including cell cycle regulation, protein kinase regulation, and cytoskeletal organization and biogenesis. Surprisingly, our results did not show a significant change in cytochrome oxidase gene expression or bioenergetics.

Inhibition and recovery of maternal and foetal cholinesterase enzymes following fenitrothion administration in CD rats.

The purpose of this study was to characterize tissue esterase activity and blood fenitrothion concentrations in the rat dam and foetus following in-utero exposure to the organophosphate insecticide fenitrothion. Time-mated, 8-week-old rats were gavaged on gestation day 19 with 0, 5, or 25 mg fenitrothion kg-1. Fenitrothion was absorbed rapidly from the gastrointestinal tract, with peak maternal and foetal blood levels observed 0.5-1.0 h after dosing. Fenitrothion concentrations in maternal and foetal blood were virtually identical and demonstrated a non-linear dose-response relationship. Acetylcholinesterase and carboxylesterase activities in maternal liver and blood and in foetal liver and brain decreased within 30-60 min of fenitrothion exposure. Esterase inhibition occurred at a fenitrothion dose (5 mg kg-1) that has not been previously associated with reproductive toxicity, suggesting that esterase inhibition should be considered as the critical effect in risk assessments for this pesticide.

Changes in intracellular pH play a secondary role in hydrogen sulfide-induced nasal cytotoxicity.

Hydrogen sulfide (H(2)S) is a naturally occurring gas that is also associated with several industries. The potential for widespread human inhalation exposure to this toxic gas is recognized as a public health concern. The nasal epithelium is particularly susceptible to H(2)S-induced pathology. Cytochrome oxidase inhibition is postulated as one mechanism of H(2)S toxicity. Another mechanism by which the weak acid H(2)S could cause nasal injury is intracellular acidification and cytotoxicity. To further understand the mechanism by which H(2)S damages the nasal epithelium, nasal respiratory and olfactory epithelial cell isolates and explants from naive rats were loaded with the pH-sensitive intracellular chromophore SNARF-1 and exposed to air or 10, 80, 200, or 400 ppm H(2)S for 90 min. Intracellular pH was measured using flow cytometry or confocal microscopy. Cell lysates were used to quantify total protein and cytochrome oxidase activity. A modest but statistically significant decrease in intracellular pH occurred following exposure of respiratory and olfactory epithelium to 400 ppm H(2)S. Decreased cytochrome oxidase activity was observed following exposure to >10 ppm H(2)S in both respiratory and olfactory epithelia. None of the treatments resulted in cytotoxicity. The intracellular acidification of nasal epithelial cells by high-dose H(2)S exposure and the inhibition of cytochrome oxidase at much lower H(2)S concentrations suggest that changes in intracellular pH play a secondary role in H(2)S-induced nasal injury.

Neurotoxicological effects associated with short-term exposure of Sprague-Dawley rats to hydrogen sulfide.

Although hydrogen sulfide (H2S) is a known neurotoxic hazard, only a limited number of experimental animal studies have examined its neurochemical or behavioral effects. Our aim was to determine if short-term inhalation exposure of rats to H2S would result in altered brain catecholamnine levels or impaired learning and memory. Three groups of adult male CD rats were tested; two groups were exposed by nose-only inhalation (0, 30, 80, 200, or 400 ppm H2S) and one group was exposed by whole-body inhalation (0, 10, 30, or 80 ppm H2S) for 3 h per day forfive consecutive days. The first group (n = 10 rats per concentration) was tested immediately following each daily nose-only H2S exposure for spatial learning with a Morris water maze. Core body temperatures were also monitored in these animals during and after the last H2S exposure. The second group of rats (n = 10 rats per concentration) was tested for spontaneous motor activity immediately following the fifth exposure. These rats were then euthanized and striatal, hippocampal, and hindbrain catecholamnine levels determined. A third group of rats (n = 5-7 rats per concentration) was pretrained on a multiple fixed- interval (FI) schedule and exposed whole-body. Daily performance on the FI schedule was compared for the week pre-exposure, for the exposure week immediately following daily exposures, and for the week postexposure. We observed significant reductions in motor activity, water maze performance, and body temperature following exposure only to high concentrations (> or = 80 ppm) of H2S. Exposure to H2S did not affect regional brain catecholamine concentrations or performance on the FI schedule. Additional studies using other measures of behavior and longer-term exposure to H2S may be required to more definitively address conditions under which H2S exposure results in behavioral toxicity.

Influence of dietary manganese on the pharmacokinetics of inhaled manganese sulfate in male CD rats.

Concerns exist as to whether individuals with relative manganese deficiency or excess may be at increased risk for manganese toxicity following inhalation exposure. The objective of this study was to determine whether manganese body burden influences the pharmacokinetics of inhaled manganese sulfate (MnSO(4)). Postnatal day (PND) 10 rats were placed on either a low (2 ppm), sufficient (10 ppm), or high (100 ppm) manganese diet. The feeding of the 2 ppm manganese diet was associated with a number of effects, including reduced body weight gain, decreased liver manganese concentrations, and reduced whole-body manganese clearance rates. Beginning on PND 77 +/- 2, male littermates were exposed 6 h/day for 14 consecutive days to 0, 0.092, or 0.92 mg MnSO(4)/m(3). End-of-exposure tissue manganese concentrations and whole-body (54)Mn elimination rates were determined. Male rats exposed to 0.092 mg MnSO(4)/m(3) had elevated lung manganese concentrations when compared to air-exposed male rats. Male rats exposed to 0.92 mg MnSO(4)/m(3) developed increased striatal, lung, and bile manganese concentrations when compared to air-exposed male rats. There were no significant interactions between the concentration of inhaled MnSO(4) and dietary manganese level on tissue manganese concentrations. Rats exposed to 0.92 mg MnSO(4)/m(3) also had increased (54)Mn clearance rates and shorter initial phase elimination half-lives when compared with air-exposed control rats. These results suggest that, marginally manganese-deficient animals exposed to high levels of inhaled manganese compensate by increasing biliary manganese excretion. Therefore, they do not appear to be at increased risk for elevated brain manganese concentrations.

Methods to identify and characterize developmental neurotoxicity for human health risk assessment. III: pharmacokinetic and pharmacodynamic considerations.

We review pharmacokinetic and pharmacodynamic factors that should be considered in the design and interpretation of developmental neurotoxicity studies. Toxicologic effects on the developing nervous system depend on the delivered dose, exposure duration, and developmental stage at which exposure occurred. Several pharmacokinetic processes (absorption, distribution, metabolism, and excretion) govern chemical disposition within the dam and the nervous system of the offspring. In addition, unique physical features such as the presence or absence of a placental barrier and the gradual development of the blood--brain barrier influence chemical disposition and thus modulate developmental neurotoxicity. Neonatal exposure may depend on maternal pharmacokinetic processes and transfer of the xenobiotic through the milk, although direct exposure may occur through other routes (e.g., inhalation). Measurement of the xenobiotic in milk and evaluation of biomarkers of exposure or effect following exposure can confirm or characterize neonatal exposure. Physiologically based pharmacokinetic and pharmacodynamic models that incorporate these and other determinants can estimate tissue dose and biologic response following in utero or neonatal exposure. These models can characterize dose--response relationships and improve extrapolation of results from animal studies to humans. In addition, pharmacologic data allow an experimenter to determine whether exposure to the test chemical is adequate, whether exposure occurs during critical periods of nervous system development, whether route and duration of exposure are appropriate, and whether developmental neurotoxicity can be differentiated from direct actions of the xenobiotic.

Androgen receptor antagonism by the organophosphate insecticide fenitrothion.

Organophosphate insecticides represent one of the most widely used classes of pesticides with high potential for human exposure in both rural and residential environments. We investigated the interaction of the organophosphothioate pesticide fenitrothion (O,O-dimethyl O-(4-nitro-m-tolyl) phosphorothioate) with the human androgen receptor (AR). Fenitrothion blocked dihydrotestosterone-dependent AR activity in a concentration-dependent and competitive manner in HepG2 human hepatoma liver cells transiently transfected with human AR and an AR-dependent luciferase reporter gene. Schild regression analysis yielded an equilibrium dissociation constant value of 2.18 x 10(-8) M. To determine the antiandrogenic potential of fenitrothion in vivo, 7-week-old castrated Sprague-Dawley rats were dosed once a day for 7 days with testosterone propionate (50 microg/day, sc) plus gavage doses of either corn oil vehicle or fenitrothion (15 or 30 mg/kg/day). An additional group of rats was given testosterone propionate and flutamide (50 mg/kg/day). Motor activity and acetylcholinesterase activity in whole blood and brain were also assessed. Both fenitrothion and the reference antiandrogen flutamide caused significant decreases in the ventral prostate, seminal vesicle, and levator ani plus bulbocavernosus muscles tissue weights. In contrast, blood acetylcholinesterase activity, a standard biomarker of organophosphate poisoning, was only inhibited at the higher dose of fenitrothion (30 mg/kg). Our results demonstrate that fenitrothion is a competitive AR antagonist, comparable in potency to the pharmaceutical antiandrogen flutamide and more potent, based on in vitro assays, than the known environmental antiandrogens linuron and p,p'-, 2,2-bis(p-hydroxyphenyl)-1,1-dichloroethylene ( p,p'-DDE).

Influence of particle solubility on the delivery of inhaled manganese to the rat brain: manganese sulfate and manganese tetroxide pharmacokinetics following repeated (14-day) exposure.

Dissolution rate can influence the pulmonary clearance of a metal and thus affect its delivery to the brain and other organs. The goal of this study was to determine the exposure-response relationship for the relatively soluble sulfate (MnSO(4)) and insoluble tetroxide (Mn(3)O(4)) forms of inhaled manganese in adult male CD rats. Rats were exposed 6 h/day for 7 days/week (14 exposures) to either MnSO(4) or Mn(3)O(4) at 0, 0.03, 0.3, or 3 mg Mn/m(3). End-of-exposure olfactory bulb, striatum, cerebellum, bile, lung, liver, femur, serum, and testes (n = 6 rats/concentration/chemical) manganese concentrations and whole-body (54)Mn elimination were then determined. Increased whole-body (54)Mn clearance rates were observed in animals from the high-dose (3 mg Mn/m(3)) MnSO(4) and Mn(3)O(4) exposure groups. Elevated manganese concentrations in the lung were observed following MnSO(4) and Mn(3)O(4) exposure to > or=0.3 mg Mn/m(3). Increased olfactory bulb and femur manganese concentrations were also observed following MnSO(4) exposure at > or=0.3 mg Mn/m(3). Elevated striatal, testes, liver, and bile manganese concentrations were observed following exposure to MnSO(4) at 3 mg Mn/m(3). Elevated olfactory bulb, striatal, femur, and bile manganese concentrations were observed following exposure to Mn(3)O(4) at 3 mg Mn/m(3). Animals exposed to MnSO(4) (3 mg Mn/m(3)) had lower lung and higher olfactory bulb and striatal manganese concentrations compared with levels achieved following similar Mn(3)O(4) exposures. Our results suggest that inhalation exposure to soluble forms of manganese results in higher brain manganese concentrations than those achieved following exposure to an insoluble form of manganese.

Pulmonary clearance of manganese phosphate, manganese sulfate, and manganese tetraoxide by CD rats following intratracheal instillation.

Manganese (Mn) is ubiquitous in ambient air due to both industrial and crustal sources. It is also a component of the octane-enhancing fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT). The combustion of MMT by the automobile engine results in the formation of Mn particulates including phosphate, sulfate, and oxide forms. The objectives of this study were to determine the contribution of particle dissolution on pulmonary clearance rates of Mn sulfate (MnSO(4)), Mn phosphate, and Mn tetraoxide (Mn(3)O(4)) in CD rats following an intratracheal instillation exposure. In addition, brain (striatal) Mn concentrations were evaluated following exposure. Adult CD rats were intratracheally instilled with 0, 0.04, 0.08, or 0.16 microg Mn/g of either MnSO(4), Mn phosphate, or Mn(3)O(4). Rats were euthanized at 0, 1, 3, or 14 days after instillation. Lung and striatal Mn concentrations were measured by neutron activation analysis. Pulmonary clearance following single intratracheal instillation of MnSO(4), Mn phosphate, or Mn(3)O(4) was similar for each of the three compounds at each of the three doses used. All pulmonary clearance half-times were less than 0.5 day. At the concentrations used, striatal Mn levels were unaffected, and lung pathology was unremarkable. The dissolution rate constant of the Mn particles was determined in vitro using lung simulant fluids. The solubility of the Mn compounds was in general 20 to 40 times greater in Hatch artificial lung lining fluid than in Gamble lung simulant fluid. The dissolution rate constant of the water-soluble MnSO(4) particles in Hatch artificial lung fluid containing protein was 7.5 x 10(-4) g (Mn)/cm(2)/day, which was 54 times that of relatively water-insoluble Mn phosphate and 3600 times that of Mn(3)O(4). The dissolution rate constants for these compounds were sevenfold slower in Gamble lung fluid simulant. For both solutions, the time for half the material to go into solution differed only by factors of 1/83 to 1/17 to 1 for MnSO(4), Mn phosphate, and Mn(3)O(4), respectively, consistent with measured differences in size distribution, specific surface, and dissolution rate constant. These data suggest that dissolution mechanisms only played a role in the pulmonary clearance of MnSO(4), while nonabsorptive (e.g., mechanical transport) mechanisms predominate for the less soluble phosphate and oxide forms of Mn.

Rudimentary hemidesmosome formation in congenital generalized junctional epidermolysis bullosa in the Sprague-Dawley rat.

Seven of 14 newborn pups in a litter of Sprague-Dawley rats were found to have generalized detachment of the epidermis, which was thin, wrinkled, and hung in loose folds over distal extremities. Histologic and ultrastructural examination of the skin showed noninflammatory separation of the epidermis from the dermis at the lamina lucida of the basement membrane zone. Ultrastructurally, hemidesmosomes were small and had a rudimentary appearance; keratin tonofilaments in basal keratinocytes were detached from the hemidesmosomes. The skin lesions were consistent with generalized junctional epidermolysis bullosa, which has not previously been reported in the rat. In humans, generalized junctional epidermolysis bullosa is most commonly caused by autosomal recessive inheritance of defective proteins of the hemidesmosomes or anchoring filaments. The specific protein defect involved in the rat lesion was not determined because fresh frozen tissue was not available.

Neurotoxicity of manganese chloride in neonatal and adult CD rats following subchronic (21-day) high-dose oral exposure.

The purpose of this study was to evaluate the relative sensitivity of neonatal and adult CD rats to manganese-induced neurotoxicity. Identical oral manganese chloride (MnCl(2)) doses (0, 25, or 50 mg kg(-1) body wt. day(-1)) were given to neonatal rats throughout lactation (i.e. from postnatal day (PND) 1 through 21) and to adult male rats for 21 consecutive days. The MnCl(2) doses administered to neonates were ca. 100-fold higher than those resulting from the consumption of an equivalent volume of rat's milk. Rats were assessed using similar behavioral and neurochemical evaluations. Several statistically significant changes occurred in Mn-exposed rats relative to control animals. Neonates given the high dose of MnCl(2) had reduced body weight gain. An increased pulse-elicited acoustic startle response amplitude was observed in neonates from both MnCl(2) treatment groups on PND 21. Increased striatal, hippocampal, hindbrain and cortical Mn concentrations were observed in all Mn-exposed neonates on PND 21. Increased hypothalamic and cerebellar Mn concentrations were also observed on PND 21 in neonates from the high-dose group only. Increased striatal, cerebellar and brain residue Mn concentrations were observed in adult rats from the high-dose group. Increased striatal dopamine and 3,4-dihydroxyphenylacetic acid levels were observed only in PND 21 neonates from the high-dose group. No treatment-related changes were observed in clinical signs, motor activity (assessed in neonates on PND 13, 17, 21 +/- 1 and in adults), passive avoidance (assessed in neonates on PND 20 +/- 1 and in adults) or neuropathology (assessed in PND 21 neonates only). The results of our experiment suggest that neonates may be at greater risk for Mn-induced neurotoxicity when compared to adults receiving similar high oral levels of Mn.

Olfactory neuron loss in adult male CD rats following subchronic inhalation exposure to hydrogen sulfide.

Dysosmia and anosmia are reported to occur following human exposure to hydrogen sulfide (H2S) gas. The clinical association between H2S exposure and olfactory dysfunction in humans necessitates evaluation of the nasal cavity and olfactory system in experimental animals used to study H2S toxicity. The purpose of this study was to subchronically expose 10-week-old male CD rats to relatively low concentrations of H2S and to histologically evaluate the nasal cavity for exposure-related lesions. Rats (n = 12/group) were exposed via inhalation to 0, 10, 30, or 80 ppm H2S 6 h/d and 7 d/wk for 10 weeks. Following exposure to 30 and 80 ppm H2S, a significant increase in nasal lesions limited to the olfactory mucosa was observed. The lesions, which consisted of olfactory neuron loss and basal cell hyperplasia, were multifocal, bilaterally symmetrical, and had a characteristic rostrocaudal distribution pattern. Regions of the nasal cavity affected included the dorsal medial meatus and the dorsal and medial portions of the ethmoid recess. The no observed adverse effect level for olfactory lesions in this study was 10 ppm. For perspective, the American Conference of Governmental Industrial Hygienists threshold limit value (TLV) recommendation for H2S is currently 10 ppm (proposed revision: 5 ppm), so the concentrations employed in the present study were 3 and 8 times the TLV. These findings suggest that subchronic inhalation exposure to a relatively low level of H2S (30 ppm) can result in olfactory toxicity in rats. However, because of differences in the breathing style and nasal anatomy of rats and humans, additional research is required to determine the significance of these results for human health risk assessment.

Pharmacokinetics of inhaled manganese phosphate in male Sprague-Dawley rats following subacute (14-day) exposure.

Methylcyclopentadienyl manganese tricarbonyl (MMT) is used as a gasoline octane enhancer. Manganese phosphate is the primary respirable (PM(2.5)) MMT-combustion product emitted from the automobile tailpipe. The goal of this study was to determine the exposure-response relationship for inhaled manganese phosphate in adult male CD rats. Rats were exposed 6-h/day for either 5 days/week (10 exposures) or 7 days/week (14 exposures) to manganese phosphate at 0, 0.03, 0.3, or 3 mg Mn/m(3) (MMAD congruent with 1.5 micrometer). The following tissues collected at the end of the 2-week exposure: plasma, erythrocytes, olfactory bulb, striatum, cerebellum, lung, liver, femur, and skeletal muscle (n = 6 rats/exposure group) were analyzed for manganese content by neutron activation analysis. Intravenous (54)MnCl(2) tracer studies were also conducted following the 14th exposure (n = 6 rats/concentration), and whole-body gamma spectrometry was performed immediately after injection and at 1, 2, 4, 8, 12, and 16 weeks after (54)MnCl(2) administration. Increased manganese concentrations were observed in olfactory bulb, lung, femur, and skeletal muscle following exposure to 3 mg Mn/m(3) (10 or 14 exposures). Increased manganese concentrations were also observed in olfactory bulb, striatum, and lung following exposure to 0.3 mg Mn/m(3) (14 exposures only). Red blood cell and plasma manganese concentrations were increased only in rats exposed to 3 mg Mn/m(3) (10 exposures). Rats exposed to 3 mg Mn/m(3) also had an increased whole-body manganese clearance rate when compared to air-exposed control animals. Our results suggest that the rat olfactory bulb may accumulate more manganese than other brain regions following inhalation exposure.

Analysis of respiratory exchange of methanol in the lung of the monkey using a physiological model.

A physiologically based pharmacokinetic (PBPK) model was developed for the monkey, to account for fractional systemic uptake of inhaled methanol vapors in the lung. Fractional uptake of inhaled [14C]-methanol was estimated using unreported exhaled breath time course measurements of [14C]-methanol from the D.C. Dorman et al. (1994, Toxicol Appl Pharmacol. 128, 229-238) lung-only exposure study. The cumulative amount of [14C]-methanol exhaled was linear with respect to exposure duration (0.5 to 2 h) and concentration (10 to 900 ppm). The model estimated that forty to eighty-one percent of the of inhaled [14C]-methanol delivered to the lung was taken into systemic circulation in female Cynomolgus monkeys exposed for two h to 10-900 ppm of [14C]-methanol. There was no apparent trend between the percent of inhaled [14C]-methanol absorbed systemically and the [14C]-methanol exposure concentration. Model simulations were conducted using a single saturable Michaelis-Menten equation with Vmaxc, the metabolic capacity set to 15.54 mg/kg/h and Km, the affinity constant, to 0.66 mg/l. The [14C]-methanol blood concentrations were variable across [14C]-methanol exposure groups and the PBPK model tended to over-predict systemic clearance of [14C]-methanol. Accounting for fractional uptake of inhaled polar solvents is an important consideration for risk assessment of inhaled polar solvents.

An integrative approach to neurotoxicology.

Exposure of human populations to a wide variety of chemicals has generated concern about the potential neurotoxicity of new and existing chemicals. Experimental studies conducted in laboratory animals remain critical to the study of neurotoxicity. An integrative approach using pharmacokinetic, neuropathological, neurochemical, electrophysiological, and behavioral methods is needed to determine whether a chemical is neurotoxic. There are a number of factors that can affect the outcome of a neurotoxicity study, including the choice of animal species, dose and dosage regimen, route of administration, and the intrinsic sensitivity of the nervous system to the test chemical. The neurotoxicity of a chemical can vary at different stages of brain development and maturity. Evidence of neurotoxicity may be highly subjective and species specific and can be complicated by the presence of systemic disease. The aim of this paper is to give an overview of these and other factors involved in the assessment of the neurotoxic potential for chemicals. This article discusses the neurotoxicity of several neurotoxicants (eg, acrylamide, trimethyltin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, manganese, and ivermectin), thereby highlighting a multidisciplinary approach to the assessment of chemically induced neurotoxicity in animals. These model chemicals produce a broad range of effects that includes peripheral axonopathy, selective neuronal damage within the nervous system, and impaired neuronal-glial metabolism.

Fertility and developmental neurotoxicity effects of inhaled hydrogen sulfide in Sprague-Dawley rats.

In this study, we examined whether perinatal exposure by inhalation to hydrogen sulfide (H2S) had an adverse impact on pregnancy outcomes, offspring prenatal and postnatal development, or offspring behavior. Virgin male and female Sprague-Dawley rats (12 rats/sex/concentration) were exposed (0, 10, 30, or 80 ppm H2S; 6 h/day, 7 days/week) for 2 weeks prior to breeding. Exposures continued during a 2-week mating period (evidence of copulation = gestation day 0 = GD 0) and then from GD 0 through GD 19. Exposure of dams and their pups (eight rats/litter after culling) resumed between postnatal day (PND) 5 and 18. Adult male rats were exposed for 70 consecutive days. Offspring were evaluated using motor activity (PND 13, 17, 21, and 60+/-2), passive avoidance (PND 22+/-1 and 62+/-3), functional observation battery (PND 60+/-2), acoustic startle response (PND 21 and 62+/-3), and neuropathology (PND 23+/-2 and 61+/-2). There were no deaths and no adverse physical signs observed in F0 male or female rats during the study. A statistically significant decrease in feed consumption was observed in F0 male rats from the 80-ppm H2S exposure group during the first week of exposure. There were no statistically significant effects on the reproductive performance of the F0 rats as assessed by the number of females with live pups, litter size, average length of gestation, and the average number of implants per pregnant female. Exposure to H2S did not affect pup growth, development, or performance on any of the behavioral tests. The results of our study suggest that H2S is neither a reproductive toxicant nor a behavioral developmental neurotoxicant in the rat at occupationally relevant exposure concentrations (< or =10 ppm).

Direct olfactory transport of inhaled manganese ((54)MnCl(2)) to the rat brain: toxicokinetic investigations in a unilateral nasal occlusion model.

Inhalation exposure of humans to high concentrations of manganese (Mn) is associated with elevated Mn levels in the basal ganglia and an extrapyramidal movement disorder. In the rat, direct olfactory transport of Mn from the nose to the brain has been demonstrated following intranasal instillation of (54)MnCl(2). However, the contribution this route makes to brain Mn delivery following inhalation is unknown and was the subject of our study. Male 8-week old CD rats underwent a single 90-min nose-only exposure to a (54)MnCl(2) aerosol (0.54 mg Mn/m(3); MMAD 2.51 microm). The left and right sides of the nose and brain, including the olfactory pathway and striatum, were sampled at 0, 1, 2, 4, and 8 days postexposure. Control rats were exposed to (54)MnCl(2) with both nostrils patent to evaluate the symmetry of Mn delivery. Another group of rats had the right nostril plugged to prevent nasal deposition of (54)MnCl(2) on the occluded side. Gamma spectrometry (n = 6 rats/group/time point) and autoradiography (n = 1 rat/group/time point) were used to compare the levels of (54)Mn found on the left and right sides of the nose and brain to determine the contribution of olfactory uptake to brain (54)Mn levels. Brain and nose samples from the side with the occluded nostril had negligible levels of (54)Mn activity, validating the nasal occlusion procedure. High levels of (54)Mn were observed in the olfactory bulb and tract/tubercle on the side or sides with an open nostril within 1-2 days following inhalation exposure. These results demonstrated, for the first time, that the olfactory route contributes the majority (up to >90%) of the (54)Mn found in the olfactory pathway, but not in the striatum, of the rat brain up to 8 days following a single inhalation exposure. These findings suggest that the olfactory route may make a significant contribution to brain Mn levels following inhalation exposure in the rat.

Manganese-induced developmental neurotoxicity in the CD rat: is oxidative damage a mechanism of action?

Inhalation of high concentrations of manganese (Mn) is associated with an extrapyramidal motor disorder in humans. Oxidative damage, mediated by increased levels of Mn in dopaminergic brain regions and mitochondria, is a hypothesized mechanism of action for Mn-induced neuronal degeneration and loss. To test this proposed mechanism, developing CD rats, which may be at an increased risk for Mn-induced neurotoxicity, were exposed orally to 0, 25, or 50 mg/kg/day of MnCl2 from postnatal day (PND) 1 to 49 Brain regional and mitochondrial Mn levels, brain regional reactive oxygen species (ROS) levels, and whole-brain nuclear and mitochondrial 8-OHdG levels were used to evaluate Mn-mediated oxidative damage. High-dose Mn exposure was associated with increased spontaneous motor activity on PND 21 and decreased body weights on PND 49. On PND 21, Mn concentrations were increased in brain regions and mitochondrial fractions in both low- and high-dose groups. ROS levels were elevated in cerebellum but not striatum. On PND 49, Mn concentrations in brain regions and mitochondrial fractions were increased only in the high-dose group. Mn exposure did not significantly alter 8-OHdG levels in either mitochondrial or nuclear DNA. Selective uptake of Mn by the striatum or mitochondrial fraction was not demonstrated at either time point. These data allow us to conclude that oral exposure to high levels of Mn in developing CD rats resulted in increased brain regional and mitochondrial Mn levels, increased motor activity, and decreased body weights but not in selective accumulation of Mn in the striatum or mitochondrial fraction of any brain region or elevations in striatal ROS or whole-brain 8-OHdG levels. These findings do not support the hypothesis that oxidative damage, as assessed by ROS and 8-OHdG levels, is a mechanism of action in Mn-induced developmental neurotoxicity in the CD rat.