Additive Methylcyclopentadienyl Manganese Tricarbonyl Research Articles

Small noncoding RNA dysregulation is implicated in manganism in a rat model of methylcyclopentadienyl manganese tricarbonyl-induced unrepaired striatum damage.

The accumulation of excessively high manganese levels within the brain can contribute to a series of Parkinsonian symptoms referred to as manganism. The gasoline antiknock additive Methylcyclopentadienyl Manganese Tricarbonyl (MMT) is an environmental source of manganese exposure and can induce manganism in rats. While some prior reports have demonstrated the differential expression of small noncoding RNAs (sncRNAs) in patients with Parkinson's disease (PD), the degree of sncRNA dysfunction in manganism has yet to be clearly documented. As sncRNAs such as transfer RNA-derived small RNAs (tsRNAs) and ribosomal RNA-derived small RNAs (rsRNAs) exhibit high levels of modifications such as 3' terminal 3'-phosphate and 2',3'-cyclic phosphate modifications that disrupt the process of adapter ligation and m1A, m3C, m1G, and m22G RNA methylation, these transcripts are not detected in traditional small RNA-sequencing studies. Here, differential sncRNA expression was analyzed by comparing a rat model of MMT-induced unrepaired striatum damage to appropriate control samples via PANDORA-Seq, which can detect highly modified sncRNAs. Following the removal of sncRNA modifications, this approach identified 599 sncRNAs that were differentially expressed in the striatum of MMT-exposed rats relative to controls, as well as 1155 sncRNAs that were differentially expressed in Mn-treated and control rats. Additional functional analyses were performed to predict the putative targets of these sncRNAs, implicating a role for such sncRNA dysregulation in the pathogenesis of manganism in this rat model system.

Methylcyclopentadienyl Manganese Tricarbonyl Alter Behavior and Cause Ultrastructural Changes in the Substantia Nigra of Rats: Comparison with Inorganic Manganese Chloride.

The antiknock additive methylcyclopentadienyl manganese tricarbonyl (MMT) is an organic manganese(Mn) compound. Mn neurotoxicity caused by occupational Mn exposure (mostly inorganic MnCl2) is associated with motor and cognitive disturbances, referred to as Manganism. However, the impact of environmentally relevant Mn exposure on MMT-induced Manganism is poorly understood. In this investigation, we studied the effects of MMT on motor function and brain structure, and compared its effects with those of inorganic MnCl2. After adaptive feeding for 7days, male and female Sprague-Dawley (SD) rats in the MMT-treated groups and positive control group were treated for 8weeks with MMT (1, 2 and 4mg/kg/i.g.) or MnCl2·4H2O (200mg/kg/i.g.). Mn content in blood, liver, spleen and distinct brain regions was determined by inductively coupled plasma-mass spectrometer (ICP-MS). We found that MMT and MnCl2 exposure led to slower body-weight-gain in female rats, impaired motor and balance function and spatial learning and memory both in male and female rats. HE staining showed that MMT and MnCl2 led to altered structure of the substantia nigra pars compacta (SNpc), and Nissl staining corroborated MMT's propensity to damage the SNpc both in male and female rat. In addition, Immunostaining of the SNpc showed decreased TH-positive neurons in MMT- and MnCl2-treated rats, concomitant with Iba1 activation in microglia. Moreover, no statistically significant difference was noted between the rats in the H-MMT and MnCl2 groups. In summary, these findings suggest that MMT and MnCl2 exposure cause ultrastructural changes in the SNpc neurons culminating in altered motor behavior and cognition, suggesting that altered SNpc structure and function may underline the motor and cognitive deficits inherent to Manganism, and accounting for MMT and MnCl2's manifestations of atypical parkinsonism.

Effects of low-dose methylcyclopentadienyl manganese tricarbonyl-derived manganese on the development of diencephalic dopaminergic neurons in zebrafish

Fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT) is counted as an organic manganese (Mn)-derived compound. The toxic effects of Mn (alone and complexed) on dopaminergic (DA) neurotransmission have been investigated in both cellular and animal models. However, the impact of environmentally relevant Mn exposure on DA neurodevelopment is rather poorly understood. In the present study, the MMT dose of 100 μM (about 5 mg Mn/L) caused up-regulation of DA-related genes in association with cell body swelling and increase in the number of DA neurons of the ventral diencephalon subpopulation DC2. Furthermore, our analysis identified significant brain Mn bioaccumulation and enhancement of total dopamine levels in association with locomotor hyperactivity. Although DA levels were restored at adulthood, we observed a deficit in the acquisition and consolidation of memory. Collectively, these findings suggest that developmental exposure to low-level MMT-derived Mn is responsible for the selective alteration of diencephalic DA neurons and with long-lasting effects on fish explorative behaviour in adulthood.

Combustion and emission characteristics of a direct-injection gasoline engine using the MMT fuel additive gasoline

In recent years, Methyl-cyclopentadienyl Manganese Tricarbonyl (MMT) has been widely used as a gasoline additive to improve the octane rating and antiknock of the fuel. Meanwhile, particulate emissions from the gasoline direct injection (GDI) engine have become a subject of concern. This study is aimed to investigate the impact of fuel (ultralow sulfur gasoline with the additive MMT) on the combustion characteristic, gaseous emissions (HC, CO and NOx) and particulate matter (PM) emissions in a GDI research engine, under the operating conditions of stoichiometric air/fuel ratio, 2000rpm engine speed and 30–150Nm engine torque. The experimental results show that, in the GDI engine, the cylinder pressure increases slightly with the increase of MMT content in the test fuels. The use of MMT increases the peak heat release rate and ignition delay slightly but the combustion duration does not change significantly. Depending on the fuel used, the HC emissions decrease significantly, while the CO and NOx emissions increase with the increase of MMT content in the test fuels. There was a measurable effect on PM emissions by the introduction of the MMT additive gasoline fuels. The total particulate mass and number concentrations significantly increase with the increase of the MMT content in the test fuels. At low and medium loads, there is little change in geometrical mean diameter of the particles, while it would become larger when the tested engine operated on the high engine condition.

Update on a Pharmacokinetic-Centric Alternative Tier II Program for MMT—Part I: Program Implementation and Lessons Learned

Concerns have been raised regarding environmental manganese exposure since high exposures have been associated with neurological disorders. The USA Environmental Protection Agency most recent human health risk assessment of inhaled manganese conducted in 1993 identified specific areas of uncertainty regarding manganese pharmacokinetics. This led to the development of a test rule under the USA Clean Air Act that required the generation of pharmacokinetic information on the inorganic manganese combustion products of the organometallic fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT). The Alternative Tier 2 testing program for MMT, described in this paper, has yielded substantial pharmacokinetic data and has enabled the generation of physiologically based pharmacokinetic (PBPK) models for manganese. These models are capable of predicting tissue manganese concentrations across a variety of dose routes, levels, and durations while accounting for factors such as age, gender, and reproductive status, enabling the consideration of tissue dosimetry in future risk assessments.

Manganese cycling in central Ontario forests: Response to soil acidification

Soil acidification results in enhanced mobilization of many potentially phytotoxic metals, including Mn. In Canada, there is also concern that emissions of Mn from the gasoline additive methylcyclopentadienyl manganese tricarbonyl (MMT) may contribute to the environmental risk posed by Mn. As a first step toward understanding the risk posed by Mn in acidifying forest systems in Ontario, the authors sampled foliage and soil from 46 forest plots in central Ontario that encompassed a soil pH range of 3.9–8.1. Increased availability of Mn at lower soil pH was clearly demonstrated, as water-extractable Mn increased and molar ratios of Ca:Mn in foliage decreased at sites with lower soil pH, although Mn availability appears to be determined by both soil pH and Mn content in soil. The cycling of Mn was studied in detail at a representative acidified coniferous forest catchment (Plastic Lake) in central Ontario. Between 1980 and 2002, Mn bulk deposition at PC ranged from 3 to 7 mg m −2 a −1 and there was no evidence that Mn deposition increased over this time period despite increased usage of MMT. Temporal patterns of Mn concentrations in stream water draining the Plastic Lake catchment were highly correlated to SO 4 2 - levels in stream water ( r 2 = 0.90), indicating that acid leaching is currently driving Mn losses. Furthermore, Mn outputs in stream water draining the terrestrial catchment exceeded bulk deposition inputs, whereas the lake was a net sink for Mn, due to retention in lake sediment. Because Mn availability is determined by soil pH and the Mn content in soil, net losses of Mn from the terrestrial catchment indicate that Mn levels in soil and stream water will ultimately decline over the long-term, and therefore Mn is unlikely to have a negative impact on forests in this region.

Blood manganese concentrations among first-grade schoolchildren in two South African cities

Little information exists on the environmental exposures to low levels of organometallic manganese (a principal combustion product from manganese-containing fuel additives) and public health. This study was undertaken to establish biological and environmental levels of manganese among first-grade schoolchildren in the South African cities of Johannesburg and Cape Town. The study was undertaken subsequent to partial introduction of the manganese-containing fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT) to South African petrol in the Johannesburg region only, about 24 months prior to the commencement of the study, and in anticipation of possible future increases in MMT use in the rest of the country.This study involved the measurement of manganese concentrations in the blood of the total number of 814 of grade one schoolchildren (430 and 384 in Cape Town and Johannesburg, respectively), and in water supplies, soil, and classroom dust at a total number of 21 participating schools. The results indicated higher concentrations of manganese in school soil (P=0.0007) and dust (P=0.0071) samples from Johannesburg relative to Cape Town. Similarly, the mean blood manganese concentration in Johannesburg study subjects (9.80μg/L, SD 3.59) was significantly higher than that in Cape Town study subjects (6.74μg/L, SD 3.47), after allowing for the clustering effect within schools and adjusting for the confounding effect of population group (P<0.0001). The blood manganese levels of 4.2% and 12.5% of children in Cape Town and Johannesburg, respectively, equaled or exceeded 14μg/L, the upper normal reference value specified by the Agency for Toxic Substances Disease Registry (ATSDR, 2000). Importantly, levels of manganese in blood were found to be significantly associated with concentrations of manganese in classroom dust at schools.

Iron interactions and other biological reactions mediating the physiological and toxic actions of manganese

Chronic exposure to the divalent heavy metals, such as iron, lead, manganese (Mn), and chromium, has been linked to the development of severe, often irreversible neurological disorders and increased vulnerability to developing Parkinson’s disease. Although the mechanisms by which these metals elicit or facilitate neuronal cell death are not well defined, neurotoxicity is limited by the extent to which they are transported across the blood–brain barrier and their subsequent uptake within targeted neurons. Once inside the neuron, these heavy metals provoke a series of biochemical and molecular events leading to cell death induced by either apoptosis and/or necrosis. The toxicological properties of Mn have been studied extensively in recent years because of the potential health risk created by increased atmospheric levels owing to the impending use of the gas additive methylcyclopentadienyl manganese tricarbonyl. Individuals exposed to high environmental levels of Mn, which include miners, welders, and those living near ferroalloy processing plants, display a syndrome known as manganism, best characterized by debilitating symptoms resembling those of Parkinson’s disease. Mn disposition in vivo is influenced by dietary iron intake and stores within the body since the two metals compete for the same binding protein in serum (transferrin) and subsequent transport systems (divalent metal transporter, DMT1). There appear to be two distinct carrier-mediated transport systems for Mn and ferrous ion: a transferrin-dependent and a transferrin-independent pathway, both of which utilize DMT1 as the transport protein. Accordingly, this commentary focuses on the biochemical and molecular processes responsible for the cytotoxic actions of Mn and the role that cellular transport plays in mediating the physiological as well as the toxicological actions of this metal.

Effect on exhaust emissions by the use of methylcyclopentadienyl manganese tricarbonyl (MMT) fuel additive and other lead replacement gasolines

This paper examines the potential effects on car exhaust emissions of a range of alternative lead replacement gasolines in the context of south European countries such as Greece. The main objective of this study was to assess the effects on emissions from non-catalyst passenger vehicles by the substitution of leaded (‘super’) gasoline with Euro95 unleaded enriched with the additive MMT or other alternative to leaded gasoline fuels. Regulated emissions, two non-regulated pollutants and vehicle performance were measured on two catalyst-equipped and two conventional, non-catalyst vehicles. It was found that there was no measurable effect on regulated emissions (CO, HC and NO x ) and on fuel consumption by the introduction of the lead replacement fuels for both catalyst and non-catalyst cars. In the case of the non-catalyst car, the shift from leaded to unleaded gasoline was associated with an increase in benzene and formaldehyde emissions, a trend probably attributable to the increased aromatics content of the lead replacement fuels.

Comprehensive characterization of engine deposits from fuel containing MMT ®

Combustion chamber deposits from a 1996 GM3800 engine operating on a base fuel or the base fuel containing the organometallic antiknock additive methylcyclopentadienyl manganese tricarbonyl were examined. Scanning Electron Microscopy and Energy Dispersive X-ray spectroscopic analysis were performed to identify the morphology and the bulk chemical composition. Glow-Discharge Mass Spectrometry and X-ray Diffraction analyses were also used to characterize the bulk chemical composition and crystalline structure of the deposits. In addition, X-ray photoemission and X-ray photoabsorption spectra for the deposits were compared to a series of Mn compounds to model and aid quantification of the constituents. Results reveal a mixture of Ca-sulfate, Mn-phosphate and Mn-oxide in the bulk of the deposits and a mixture of Mn-sulfate, Mn-phosphate and Mn-oxide on the surface of the deposits.

ASSESSMENT OF BIOACCUMULATION AND NEUROTOXICITY IN RATS WITH PORTACAVAL ANASTOMOSIS AND EXPOSED TO MANGANESE PHOSPHATE: A PILOT STUDY

The use of the additive methylcyclopentadienyl manganese tricarbonyl in unleaded gasoline has resulted in increased attention to the potential toxic effects of manganese (Mn). Hypothetically, people with chronic liver disease may be more sensitive to the adverse neurotoxic effects of Mn. In this work, bioaccumulation of Mn, as well as histopathology and neurobehavioral damage, in end-to-side portacaval anastomosis (PCA) rats exposed to Mn phosphate via inhalation was investigated. During the week before the PCA operation, 4 wk after the PCA operation, and at the end of exposure, the rats were subjected to a locomotor evaluation (day-night activities) using a computerized autotrack system. Then a group of 6 PCA rats (EXP) was exposed to 3050 µg m -3 (Mn phosphate) for 8 h/day, 5 days/wk for 4 consecutive weeks and compared to a control group (CON), 7 PCA rats exposed to 0.03 µg m -3. After exposure, the rats were euthanized and Mn content in tissues and organs was determined by neutron activation analysis. The manganese concentrations in blood (0.05 µg/g vs. 0.02 µg/g), lung (1.32 µg/g vs. 0.24 µg/g), cerebellum (0.85 µg/g vs. 0.64 µg/g), frontal cortex (0.87 µg/g vs. 0.61 µg/g), and globus pallidus (3.56 µg/g vs. 1.33 µg/g) were significantly higher in the exposed group compared to the control group (p < .05). No difference was observed in liver, kidney, testes, and caudate putamen between the two groups. Neuronal cell loss was assessed by neuronal cell counts. The loss of cells in globus pallidus and caudate putamen as well as in frontal cortex was significantly higher (p < .05) for the EXP group. Assessment of the locomotor activities did not reveal any significant difference. This study constitutes a first step toward our understanding of the potential adverse effects of Mn in sensitive populations.

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.

Analysis of manganese particulates from automotive decomposition of methylcyclopentadienyl manganese tricarbonyl

Particulates have been collected and analyzed from automotive vehicles operating on fuel containing the organometallic antiknock additive methylcyclopentadienyl manganese tricarbonyl. Electron spectroscopy for chemical analysis and L-edge X-ray absorption spectroscopy were used to study and identify the manganese species present in these emitted particulates. Results show that respirable size particulates with a mass median aerodynamic diameter of 2.5 μm or less (PM 2.5) in vehicle exhaust contain manganese primarily in the form of a manganese phosphate and/or sulfate.

Determination of methylcyclopentadienylmanganese tricarbonyl (MMT) in aqueous samples by SPME-GC-AED

Solid phase microextraction (SPME) was successfuly applied to the determination of the gasoline additive methylcyclopentadienylmanganese tricarbonyl (MMT) in aqueous samples. The procedure is simple, efficient and solvent free. Ultra-trace levels of MMT (pg l–1) in water can be determined with the combination of SPME and gas chromatography–plasma atomic emission detection. The linear range is between 1 and 1000 pg l–1 with relative detection limits of 0.3 pg l–1 (as Mn) of MMT in water. The precision for replicate analyses (n = 4) of an MMT solution (10 pg l–1 as Mn) was 7.1% (RSD). Different kinds of aqueous samples were collected and extracted for the determination of MMT with the SPME technique. In spite of its short half-life in the presence of light, MMT was found in all highway runoff and sewage samples. The liquid–liquid extraction method was also used for MMT determination in highway runoff and lake water samples and the results from the two techniques were comparable.

Canada capitulates on MMT, settles with Ethyl

On July 20, the Canadian government withdrew its ban on the gasoline additive methylcyclopentadienyl manganese tricarbonyl (MMT), which it imposed last year on the grounds that the additive interferes with automobile onboard diagnostic systems. MMT's sole manufacturer, Ethyl Corp., Richmond, Va., had filed suit under the North American Free Trade Agreement (NAFTA) seeking to have the ban overturned. Advised by its lawyers that it likely would lose the suit, Canada settled. The terms of the settlement require Canada to pay Ethyl $13 million for lost profits in return for Ethyl's withdrawal of its $250 million lawsuit. This decision by the Canadian government supports current scientific information that does not impair the proper functioning of automobile emission controls, Ethyl says in a statement. It also notes that MMT poses no risk to human health. Not all agree. Automakers persist in claiming that the compound, which enhances octane ratings, interferes with emission-control systems and thus le...

Methylcyclopentadienyl manganese tricarbonyl: health risk uncertainties and research directions.

With the way cleared for increased use of the fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT) in the United States, the issue of possible public health impacts associated with this additive has gained greater attention. In assessing potential health risks of particulate Mn emitted from the combustion of MMT in gasoline, the U.S. Environmental Protection Agency not only considered the qualitative types of toxic effects associated with inhaled Mn, but conducted extensive exposure-response analyses using various statistical approaches and also estimated population exposure distributions of particulate Mn based on data from an exposure study conducted in California when MMT was used in leaded gasoline. Because of limitations in available data and the need to make several assumptions and extrapolations, the resulting risk characterization had inherent uncertainties that made it impossible to estimate health risks in a definitive or quantitative manner. To support an improved health risk characterization, further investigation is needed in the areas of health effects, emission characterization, and exposure analysis.

Investigation of MMT adsorption on soils by Diffuse Reflectance Infrared Spectroscopy (DRIFTS) and Headspace Analysis Gas-phase Infrared Spectroscopy (HAGIS)

Diffuse reflectance infrared Fourier-transform spectroscopy (DRIFTS) and headspace analysis gas-phase infrared spectroscopy (HAGIS) were used to investigate interactions between soils and the gasoline additive methylcyclopentadienylmanganese tricarbonyl (MMT). Various soil samples, as well as alumina and silica substrates, were studied. Each substrate exhibited a splitting or broadening of the degenerate e v(CO) band of MMT, suggesting an interaction involving one or two of the CO ligands. The adsorption was shown to be reversible under relatively mild conditions using HAGIS. The proposed interaction is of the Bronsted type, involving the carbonyl oxygen and a surface-bound water or hydroxyl group. This type of interaction could stabilize MMT by inhibiting photo-ejection of CO ligands, a common first step in the decomposition of organometallic carbonyl compounds such as MMT.

Risk assessment for combustion products of the gasoline additive MMT in Canada

Methylcyclopentadienyl manganese tricarbonyl (MMT) has been used as an octane enhancer in Canadian gasoline since 1976. The main potential health concern is from manganese oxides produced on combustion (mainly Mn3O4), given the known neurotoxicity of chronic inhalation of manganese (Mn) dust from mining and industrial use. Relevant epidemiological studies of occupational exposure to respirable Mn are briefly reviewed; an ambient air reference value of 0.1 μg Mn/m3, and associated inhalation tolerable daily intake (TDI) and tolerable daily uptake (TDU) of 0.035 and 0.021 μg/kg b.w./day are derived. Ambient levels of PM2.5 (respirable) Mn in Canadian cities have remained unchanged or have decreased between 1986 and 1992, and do not reflect large changes in MMT usage during that time. Ambient levels of PM10 Mn in Canadian cities in 1992 were ≤0.025 μg Mn/m3. Mean, 90th and 98th percentiles of PM10 Mn inhalation uptake based on ambient monitoring data from high traffic areas and from estimates of personal exposure are below the inhalation uptake criterion. An assessment of exposure from air, food, water and soil revealed that <1% of total daily Mn uptake is derived from inhalation for all age groups. Therefore, based on current information, Mn derived from the combustion of MMT-containing gasoline is unlikely to represent a significant health risk to Canadians.

Detection of the Engine Anti-Knock Additive Methylcyclopentadienyl Manganese Tricarbonyl (MMT) from Unleaded Gasoline in Soil by Diffuse Reflectance Infrared Fourier Transform Spectroscopy and Mass Spectrometry

Soil samples were washed with dilute solutions of the toxic anti-knock fuel additive methylcyclopentadienyl manganese tricarbonyl (MMT) in hexanes and commercial unleaded gasoline. Diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) was then used to detect the v(CO) modes of MMT, and subsequently 13CO-enriched MMT, in the soil samples. The presence of MMT in the soils was further confirmed by mass spectrometry. Concentrations corresponding to ∼10 ppm Mn in soil could be detected by DRIFTS of the dry samples, and, most interestingly, there was no evidence of significant MMT decomposition over a period of eight months. Apparently, MMT is stabilized by physisorption onto the soils. In the absence of such stabilization, however, MMT undergoes photolytic and thermal decomposition in a matter of minutes. These results suggest the possibility of longer-term environmental problems associated with gasoline spills containing MMT than was previously suspected.