Bioaccumulation and locomotor effects of manganese phosphate/sulfate mixture in Sprague-Dawley rats following subchronic (90 days) inhalation exposure

Salehi, Fariba; Krewski, Daniel; Mergler, Donna; Normandin, Louise; Kennedy, G.; Philippe, Suzanne; Zayed, Joseph

doi:10.1016/s0041-008x(03)00238-2

Cited by 49 publications

(36 citation statements)

References 22 publications

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“…High cumulative doses are not scalable to lower levels of exposure because they elicit different kinds of effects, suggesting different underlying mechanisms of toxicity. Further, because inhalation studies in rodents show toxic effects at cumulative doses even lower than those where occupationally exposed humans start to show adverse effects (Salehi et al, 2003;Tapin et al, 2005, Figure 1) the most adequate animal studies to address lifetime low level exposure in humans should administer a range of cumulative doses lower that those measured in occupational settings.…”

Section: Discussionmentioning

confidence: 99%

“…Clearly, the homeostatic capacity was exceeded in these animal studies because when reported, brain manganese concentrations were always elevated, even in the studies with the lowest cumulative doses (Bull 1978;Normandin et al 2002;Salehi et al 2003;Subhash and Padmashree 1991;Tapin et al 2005). Similarly, in monkey studies where adverse effects were detected below 40 mg Mn/Kg, manganese administration was via several high manganese content injections that most likely exceeded homeostatic regulation and produced elevated brain manganese levels (Newland et al 1989).…”

mentioning

confidence: 98%

“…Thus, the extent to which these animal studies may be of utility to understand the risk for adverse effects in humans suffering chronic low-level environmental exposures is not clear. Some recent animal studies have started to address the potential effects of low-level environmental exposures by administering environmentally relevant doses via exposure routes important in humans, though these studies are relatively few in number (Dorman et al 2005;Normandin et al 2002Normandin et al , 2004Salehi et al 2003;Tapin et al 2005).…”

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confidence: 99%

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Adequacy and Consistency of Animal Studies to Evaluate the Neurotoxicity of Chronic Low-Level Manganese Exposure in Humans

Gwiazda

Lucchini

Smith

2007

Journal of Toxicology and Environmental Health, Part A

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The adequacy of existing animal studies to understand the effects of chronic low-level manganese exposures in humans is unclear. Here, a collection of subchronic to chronic rodent and non-human primate studies was evaluated to determine whether there is a consistent dose -response relationship among studies, whether there is a progression of effects with increasing dose, and whether these studies are adequate for evaluating the neurotoxicity of chronic low-level manganese exposures in humans. Neurochemical and behavioral effects were compared along the axis of estimated internal cumulative manganese dose, independent of the route of exposure. In rodents, motor effects emerged at cumulative doses below those where occupationally exposed humans start to show motor deficits. The main neurochemical effects in rodents were an increase in striatal GABA concentration throughout the internal cumulative dose range of 18 to 5300 mg Mn/Kg but a variable effect on striatal dopamine concentration emerging at internal cumulative doses above ~200 mg Mn/Kg. Monkey studies showed motor deficits and effects on the globus pallidus at relatively low doses and consistent harmful effects on both the globus pallidus and the caudate and putamen at higher doses (> 260 mg Mn/Kg). Internal cumulative manganese doses of animal studies extend more than two orders of magnitude (<1 to 5300 mg Mn/Kg) above the doses at which occupationally exposed humans show neurological dysfunction (10-15 mg Mn/Kg). Since the animal data indicate that manganese neurotoxicity may be different at low compared to elevated exposures, most existing animal model studies might be of 3 limited relevance for the risk assessment of chronic low-level manganese exposure to humans. 4

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Section: Discussionmentioning

confidence: 99%

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confidence: 98%

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confidence: 99%

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Adequacy and Consistency of Animal Studies to Evaluate the Neurotoxicity of Chronic Low-Level Manganese Exposure in Humans

Gwiazda

Lucchini

Smith

2007

Journal of Toxicology and Environmental Health, Part A

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“…A recent study also described a potential neuro-distributions [14,16,18,21]. In chicks, Mn administoxicity model of Mn in broiler chicks [10].…”

Section: Mn In Man and Animals Include Disturbances Of Locomotormentioning

confidence: 99%

“…Plasma, mainly rats and mice [4][5][6][7][8] with few studies in the bone and tissue levels of Mn are additionally used as avian species [9,10]. The neurobehavioral effects of diagnostic or biomarker endpoints of exposure [21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Single intramuscular dose toxicokinetics of manganese in broiler chicks

Al-Zubaidy¹,

Mohammad²

2012

Vet. World

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Aim: Manganese (Mn) produces neurobehavioral toxicity in various animal species including the young chicks. The present study examines toxicokinetics of Mn in 7-10-day old chicks after an intramuscular injection at 20 mg/kg. Materials and Methods: Samples of the blood, whole brain, liver and kidney were obtained from chicks (5/each time period) at 0 time (base-line) and then at times between 0.17 to 4 h. The concentrations of Mn in the plasma and tissues were determined by atomic absorption spectrometry. Toxicokinetic parameters of Mn were calculated from the mean metal concentrations in the plasma by a non-compartmental analysis using a Windows-based computer program. Results: Injection of Mn significantly increased the metal levels in the plasma, whole brain, liver and kidney of the chicks when compared to respective base-line control values at times 0.17 to 4 h after the injection (with the exception at 2 and 4 h in the brain). The highest concentration of Mn in the plasma and the whole brain appeared one h after the injection, whereas those of the liver and kidney appeared 4 h post-injection. The concentrations of Mn in the plasma ranged between 0.43 to 1.2 µg/ml within 0.17 to 4 h. Those of the whole brain, liver and kidney were 0.11-0.46, 6.3-15 and 5.3-22.9 µg/g, respectively. The elimination half-life of Mn was 3.02 h with steady state volume of distribution 24.34 L/kg and total body clearances of 4.78 L/h/kg. The mean residence time of Mn was 5.09 h and its area under the plasma concentration-time curve (0-) was 4.18 µg.h/ml. The elimination half-life of Mn from the brain was 3.12 h with an elimination rate constant of 0.22 h-1. Conclusion: The data suggest that Mn is well absorbed and rapidly distributed after an intramuscular administration in chicks and further support the reported neurobehavioral toxic effects of the metal which are observed within one h after treatment.

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Neuropathology, tremor and electromyogram in rats exposed to manganese phosphate/sulfate mixture

Salehi

Normandin

Krewski

et al. 2006

J of Applied Toxicology

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In Canada, Methylcyclopentadienyl manganese tricarbonyl (MMT) replaced tetraethyl lead in gasoline as an antiknock agent from 1976 until 2003. The combustion of MMT leads to increased manganese (Mn) concentrations in the atmosphere, and represents one of the main sources of human exposure to Mn. The nervous system is the major target of the toxicity of Mn and Mn compounds. The purpose of this study was to investigate exposure-response relationships for neuropathology and tremor, and the associated electromyogram (EMG), following subchronic inhalation exposure of rats to a mixture of Mn phosphate/sulfate particles. Rats were exposed 6 h per day, 5 days per week for 13 consecutive weeks at 30, 300 or 3000 microg m(-3) Mn phosphate/sulfate mixture and compared with controls. Half of the rats had EMG electrodes implanted in the gastrocnemius muscle of the hind limb to assess tremor at the end of Mn exposure. Two days after the end of Mn exposure, rats were killed by exsanguination and Mn concentrations in the brain (caudate putamen, globus pallidus and frontal cortex) were determined by neutron activation analysis while neuropathology was assessed by counting neuronal cells in 2.5 mm x 2.5 mm grid areas. Increased Mn concentrations were observed in all brain sections at the highest level of exposure. The neuronal cell loss was significantly different in the globus pallidus and the caudate putamen at the highest level of exposure (3000 microg m(-3)). No sign of tremor was observed among the rats. In conclusion, exposure to a high level of Mn phosphate/sulfate mixture brought on neuropathological changes in a specific area of the brain; however, no sign of tremor was observed.

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Bioaccumulation and locomotor effects of manganese phosphate/sulfate mixture in Sprague-Dawley rats following subchronic (90 days) inhalation exposure

Cited by 49 publications

References 22 publications

Adequacy and Consistency of Animal Studies to Evaluate the Neurotoxicity of Chronic Low-Level Manganese Exposure in Humans

Adequacy and Consistency of Animal Studies to Evaluate the Neurotoxicity of Chronic Low-Level Manganese Exposure in Humans

Single intramuscular dose toxicokinetics of manganese in broiler chicks

Neuropathology, tremor and electromyogram in rats exposed to manganese phosphate/sulfate mixture

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