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Toxicology Research Accepted Manuscript
Toxicology Research Volume 1 | Number 00 | May 2012 | Pages 0000–0000
www.rsc.org/toxicology
This is an Accepted Manuscript, which has been through the RSC Publishing peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, which is prior to technical editing, formatting and proof reading. This free service from RSC Publishing allows authors to make their results available to the community, in citable form, before publication of the edited article. This Accepted Manuscript will be replaced by the edited and formatted Advance Article as soon as this is available. To cite this manuscript please use its permanent Digital Object Identifier (DOI®), which is identical for all formats of publication. More information about Accepted Manuscripts can be found in the Information for Authors.
ISSN 2045-452X
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Please note that technical editing may introduce minor changes to the text and/or graphics contained in the manuscript submitted by the author(s) which may alter content, and that the standard Terms & Conditions and the ethical guidelines that apply to the journal are still applicable. In no event shall the RSC be held responsible for any errors or omissions in these Accepted Manuscript manuscripts or any consequences arising from the use of any information contained in them.
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Journal Name
Toxicology Research
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Cite this: DOI: 10.1039/c0xx00000x
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Mechanisms of Lead and Manganese Neurotoxicity April P. Neala and Tomas R. Guilarte*b Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x
Human exposure to neurotoxic metals is a global public health problem. Metals which cause neurological toxicity, such as lead (Pb) and manganese (Mn), are of particular concern due to the long-lasting and possibly irreversible nature of their effects. Pb exposure in childhood can result in cognitive and behavioural deficits in children. These effects are long-lasting and persist into adulthood even after Pb exposure has been reduced or eliminated. While Mn is an essential element of the human diet and serves many cellular 10 functions in the human body, elevated Mn levels can result in a Parkinson’s disease (PD)-like syndrome and developmental Mn exposure can adversely affect childhood neurological development. Due to the ubiquitous presence of both metals, reducing human exposure to toxic levels of Mn and Pb remains a world-wide public health challenge. In this review we summarize the toxicokinetics of Pb and Mn, describe their neurotoxic mechanisms, and discuss common themes in their neurotoxicity. 15
a
US FDA, College Park, MD E-mail:[email protected] Dept. of Env. Health Sci., Mailman School of Public Health, Columbia University, New York, NY 10032. Phone: 212-305-3959 Fax: 212-305-3857 Email: [email protected] *Corresponding author b
Introduction It has been estimated that 1 billion people in the world suffer from some form of disability.(1) Of the top 20 health conditions resulting in disability, one quarter are neurological.(1) Furthermore, it has 25 recently been estimated that the global prevalence of intellectual disability may be as high as 1%(2) and mental disability prevalence rates were twice as high in developing countries as found in developed countries. Environmental factors, such as maternal 30 and child health care, immunizations, and environmental pollution, can influence the prevalence of mental disability.(2) Thus, poorer health quality and higher contamination levels of pollutants in developing countries may contribute to the higher 35 prevalence rates. A prime factor implicated in cognitive and neurological deficits is environmental exposure to metals. Exposure to neurotoxic metals can occur through contaminated air, food, water, or in 40 hazardous occupations. While the levels of neurotoxic metal contamination of the environment have decreased in recent decades in the developed world, the developing world experiences high levels of metal pollution. In particular, Asian and African 45 countries have high levels of metal contamination, especially in urban environments.(3,4) This contamination largely derives from anthropogenic sources, such as the combustion of leaded gasoline or unregulated industrial emissions. There is also a 20
This journal is © The Royal Society of Chemistry [year]
significant problem with metal contamination from mining in developing countries, which results in elevated metal levels in water and air.(5-7) Another major source of metal contamination in developing countries is the practice of electronic waste recycling. 55 Electronic waste, which is composed of used or broken computers, mobile phones, and other electronic devices, contains valuable metals such as copper and gold. This waste is exported from developed countries for disposal in developing 60 countries, where few regulations are in place regarding safe disposal.(8) Unfortunately, unsafe methods are used for the extraction of the precious metals, resulting in contamination of the local environment of highly toxic metals such as mercury (7,9,10) 65 and lead. Due to the toxic nature of many of the chemicals and metals found in electronic waste, this pollution may have lasting detrimental effects on the neurodevelopment of children.(11) The metals lead (Pb) and manganese (Mn) 70 have both been shown to induce cognitive and behavioural deficits in adults and children with elevated levels of exposure.(12-15) While Mn has many physiological functions in the human body, elevated Mn levels can result in a neurological syndrome 75 similar to Parkinson’s disease and developmental Mn exposure can adversely affect childhood neurological development. In contrast, Pb has no known physiological function and all known effects of Pb are detrimental to humans. While both metals can 50
[journal], [year], [vol], 00–00 | 1
Toxicology Research Accepted Manuscript
Downloaded on 08 January 2013 Published on 03 January 2013 on http://pubs.rsc.org | doi:10.1039/C2TX20064C
5
Toxicology Research
Page 2 of 17
Lead (Pb) Pb exposure has received world-wide attention due to its ability to cause behavioural and cognitive deficits in exposed children. The dose-response of Pb effects on the intelligence quotient (IQ) of children is nonlinear, with lower exposures of Pb resulting in a (14,16,17) 15 greater rate of IQ loss than at higher exposures. These studies indicate that the majority of the estimated IQ loss in Pb-exposed children occurs during the first 10 µg/dL of exposure, and suggest that Pb may be a non-threshold neurotoxicant.(14,16,17) 20 Due to these effects, there have been global initiatives to reduce the use of Pb, but despite these efforts Pb exposure remains a widespread problem.(18,19)
Downloaded on 08 January 2013 Published on 03 January 2013 on http://pubs.rsc.org | doi:10.1039/C2TX20064C
10
Pb2+ Exposure
In the United States, a Pb4+-derived antiknock agent (tetraethyl Pb) was once commonly added to petrol-based fuel to improve engine efficiency. However, major concerns regarding Pb exposure and its adverse effect on child neurological (20,21) 30 function ultimately resulted in the reduction and eventual ban of leaded fuel. Analysis of population blood lead levels (BLLs) show that as Pb was removed from gasoline, BLLs dropped significantly.(22-25) In a meta-analysis of 17 studies 35 from 5 continents, the average BLL after removal of Pb from gasoline was estimated to be 3 µg/dL.(26) This value is close to the current US population average BLL(27) and levels estimated in isolated populations,(28) and may indicate background Pb 40 exposure from sources other than emissions from combustion of leaded gasoline. Alternative airborne sources of Pb exposure include primary and secondary smelters and piston-engine aircraft, which still use Pb-containing gasoline.(29) 45 As a result of evidence that Pb in paint could cause neurological deficits when ingested by children, Pb was removed from paint in Europe in 1922 and in the United States in 1978.(30,31) However, banning the sale of leaded paint did not remove the 50 threat of Pb contamination in homes already containing leaded paint. Many homes in the United States still contain leaded paint,(31,32) especially in city centers.(33) Chipped and peeling leaded paint 25
2 | Journal Name, [year], [vol], 00–00
constitutes a major source of current childhood Pb 55 exposure, as the desiccated paint can easily disintegrate at friction surfaces to form Pb dust.(34,35) Pb dust can also be formed from the combustion of leaded fuels; previous emissions of leaded fuel resulted in a massive dispersion of Pb dust in the 60 environment, especially along roadways.(36) Particulate Pb is characteristically fine (2-10 µm),(36) does not degrade, and continues to be a major source of human exposure.(33,37) Drinking water can be another source of 65 environmental Pb exposure. Leaching of Pb into drinking water occurs from outdated fixtures and solders containing Pb. The significance of Pb leaching into drinking water was emphasized during the 2001 Washington, DC, “Lead in drinking water 70 crisis,” when leaching of Pb from pipes into drinking water rapidly increased the amount of Pb contamination, resulting in a 9.6 fold increase in the incidence of elevated blood Pb levels in children.(38) This unfortunate incident highlights the role 75 contaminated drinking water can play in overall childhood Pb exposure. The current action level for Pb in water has been set at 15 ppb (15 µg/L) by the United States Environmental Protection Agency (EPA). Although the majority of water suppliers in 80 the United States are in compliance with this action level, children can still be exposed to Pb levels higher than 15 ppb (15 µg/L) if the plumbing contains leaded components that do not have optimized corrosion control. Without optimized corrosion 85 control systems, Pb can leach into drinking water from leaded plumbing components. Furthermore, not all water systems are subject to EPA regulation; for example, well water is not subject to the 15 ppb (15 µg/L) action level and is not routinely tested for Pb 90 levels. It is estimated that up to 45 million people in the United States drink water that is not subject to EPA regulations. The Pb exposure from drinking water remain unknown in these water systems.(39) Due to the success of environmental 95 interventions regarding Pb, childhood Pb exposure in the US has decreased since the 1970’s. The most recent evidence indicates that contemporary childhood BLLs in the US are on the order of 1.9 µg/dL while the percentage of children with elevated (27) 100 BLLs (above 10 µg/dL) has dropped to 1.4%. Peak BLLs occur when children are roughly 2 years of age.(14,17,40,41) Significant decreases in BLLs have been observed in this age group as well: average BLLs have decreased to 2.1 µg/dL and the percentage of 105 children in this age group with elevated BLLs dropped to 2.4%.(27) Thus, the contemporary exposure This journal is © The Royal Society of Chemistry [year]
Toxicology Research Accepted Manuscript
View Article Online
result in distinct neurological effects, with different brain targets and modes of action, they share a key similarity in that they both disrupt synaptic transmission. The aims of this review are to 5 summarize the toxicokinetics of Pb and Mn, describe their neurotoxic mechanisms, and discuss common themes in their neurotoxicity.
Page 3 of 17
Toxicology Research
Downloaded on 08 January 2013 Published on 03 January 2013 on http://pubs.rsc.org | doi:10.1039/C2TX20064C
Pb Toxicokinetics
The main routes of exposure for Pb are inhalation and ingestion. Inhalation exposure to Pb is a much more 15 efficient route of absorption than ingestion, with an estimated absorption efficiency ratio of 10 to 1 in the lung compared to the GI tract.(43,44) Due to the reduction in use of leaded gasoline, inhalation exposure in developed countries is generally limited 20 to people who live near smelters and to workers in occupational settings.(45,46) Pb can adsorb onto particulate matter (PM) and thus be inhaled. Inhalation studies classify PM by size; PM10 contains PM of aerodynamic diameter ≤ 10 µm, while 25 PM2.5 contains PM of aerodynamic diameter ≤2.5 µm.The deposition of inhaled inorganic Pb is dependent on particle size and composition. Particles >2.5 µm are deposited in the upper airways and can be cleared via mucociliary clearance. Particles
Downloaded on 08 January 2013 Published on 03 January 2013 on http://pubs.rsc.org | doi:10.1039/C2TX20064C
Toxicology Research Accepted Manuscript
Toxicology Research Volume 1 | Number 00 | May 2012 | Pages 0000–0000
www.rsc.org/toxicology
This is an Accepted Manuscript, which has been through the RSC Publishing peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, which is prior to technical editing, formatting and proof reading. This free service from RSC Publishing allows authors to make their results available to the community, in citable form, before publication of the edited article. This Accepted Manuscript will be replaced by the edited and formatted Advance Article as soon as this is available. To cite this manuscript please use its permanent Digital Object Identifier (DOI®), which is identical for all formats of publication. More information about Accepted Manuscripts can be found in the Information for Authors.
ISSN 2045-452X
XXXXXXXXXXXX Xxxx Xxxxx xxxXxxx Xxxxx Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxx
XXXXXXXXXXXX Xxxx Xxxxx xxxXxxx Xxxxx Xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx xxxxxxxxxxxxx
Please note that technical editing may introduce minor changes to the text and/or graphics contained in the manuscript submitted by the author(s) which may alter content, and that the standard Terms & Conditions and the ethical guidelines that apply to the journal are still applicable. In no event shall the RSC be held responsible for any errors or omissions in these Accepted Manuscript manuscripts or any consequences arising from the use of any information contained in them.
www.rsc.org/toxicology Registered Charity Number 207890
Page 1 of 17
Journal Name
Toxicology Research
Dynamic Article Links ► View Article Online
Cite this: DOI: 10.1039/c0xx00000x
ARTICLE TYPE
www.rsc.org/xxxxxx
Mechanisms of Lead and Manganese Neurotoxicity April P. Neala and Tomas R. Guilarte*b Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x
Human exposure to neurotoxic metals is a global public health problem. Metals which cause neurological toxicity, such as lead (Pb) and manganese (Mn), are of particular concern due to the long-lasting and possibly irreversible nature of their effects. Pb exposure in childhood can result in cognitive and behavioural deficits in children. These effects are long-lasting and persist into adulthood even after Pb exposure has been reduced or eliminated. While Mn is an essential element of the human diet and serves many cellular 10 functions in the human body, elevated Mn levels can result in a Parkinson’s disease (PD)-like syndrome and developmental Mn exposure can adversely affect childhood neurological development. Due to the ubiquitous presence of both metals, reducing human exposure to toxic levels of Mn and Pb remains a world-wide public health challenge. In this review we summarize the toxicokinetics of Pb and Mn, describe their neurotoxic mechanisms, and discuss common themes in their neurotoxicity. 15
a
US FDA, College Park, MD E-mail:[email protected] Dept. of Env. Health Sci., Mailman School of Public Health, Columbia University, New York, NY 10032. Phone: 212-305-3959 Fax: 212-305-3857 Email: [email protected] *Corresponding author b
Introduction It has been estimated that 1 billion people in the world suffer from some form of disability.(1) Of the top 20 health conditions resulting in disability, one quarter are neurological.(1) Furthermore, it has 25 recently been estimated that the global prevalence of intellectual disability may be as high as 1%(2) and mental disability prevalence rates were twice as high in developing countries as found in developed countries. Environmental factors, such as maternal 30 and child health care, immunizations, and environmental pollution, can influence the prevalence of mental disability.(2) Thus, poorer health quality and higher contamination levels of pollutants in developing countries may contribute to the higher 35 prevalence rates. A prime factor implicated in cognitive and neurological deficits is environmental exposure to metals. Exposure to neurotoxic metals can occur through contaminated air, food, water, or in 40 hazardous occupations. While the levels of neurotoxic metal contamination of the environment have decreased in recent decades in the developed world, the developing world experiences high levels of metal pollution. In particular, Asian and African 45 countries have high levels of metal contamination, especially in urban environments.(3,4) This contamination largely derives from anthropogenic sources, such as the combustion of leaded gasoline or unregulated industrial emissions. There is also a 20
This journal is © The Royal Society of Chemistry [year]
significant problem with metal contamination from mining in developing countries, which results in elevated metal levels in water and air.(5-7) Another major source of metal contamination in developing countries is the practice of electronic waste recycling. 55 Electronic waste, which is composed of used or broken computers, mobile phones, and other electronic devices, contains valuable metals such as copper and gold. This waste is exported from developed countries for disposal in developing 60 countries, where few regulations are in place regarding safe disposal.(8) Unfortunately, unsafe methods are used for the extraction of the precious metals, resulting in contamination of the local environment of highly toxic metals such as mercury (7,9,10) 65 and lead. Due to the toxic nature of many of the chemicals and metals found in electronic waste, this pollution may have lasting detrimental effects on the neurodevelopment of children.(11) The metals lead (Pb) and manganese (Mn) 70 have both been shown to induce cognitive and behavioural deficits in adults and children with elevated levels of exposure.(12-15) While Mn has many physiological functions in the human body, elevated Mn levels can result in a neurological syndrome 75 similar to Parkinson’s disease and developmental Mn exposure can adversely affect childhood neurological development. In contrast, Pb has no known physiological function and all known effects of Pb are detrimental to humans. While both metals can 50
[journal], [year], [vol], 00–00 | 1
Toxicology Research Accepted Manuscript
Downloaded on 08 January 2013 Published on 03 January 2013 on http://pubs.rsc.org | doi:10.1039/C2TX20064C
5
Toxicology Research
Page 2 of 17
Lead (Pb) Pb exposure has received world-wide attention due to its ability to cause behavioural and cognitive deficits in exposed children. The dose-response of Pb effects on the intelligence quotient (IQ) of children is nonlinear, with lower exposures of Pb resulting in a (14,16,17) 15 greater rate of IQ loss than at higher exposures. These studies indicate that the majority of the estimated IQ loss in Pb-exposed children occurs during the first 10 µg/dL of exposure, and suggest that Pb may be a non-threshold neurotoxicant.(14,16,17) 20 Due to these effects, there have been global initiatives to reduce the use of Pb, but despite these efforts Pb exposure remains a widespread problem.(18,19)
Downloaded on 08 January 2013 Published on 03 January 2013 on http://pubs.rsc.org | doi:10.1039/C2TX20064C
10
Pb2+ Exposure
In the United States, a Pb4+-derived antiknock agent (tetraethyl Pb) was once commonly added to petrol-based fuel to improve engine efficiency. However, major concerns regarding Pb exposure and its adverse effect on child neurological (20,21) 30 function ultimately resulted in the reduction and eventual ban of leaded fuel. Analysis of population blood lead levels (BLLs) show that as Pb was removed from gasoline, BLLs dropped significantly.(22-25) In a meta-analysis of 17 studies 35 from 5 continents, the average BLL after removal of Pb from gasoline was estimated to be 3 µg/dL.(26) This value is close to the current US population average BLL(27) and levels estimated in isolated populations,(28) and may indicate background Pb 40 exposure from sources other than emissions from combustion of leaded gasoline. Alternative airborne sources of Pb exposure include primary and secondary smelters and piston-engine aircraft, which still use Pb-containing gasoline.(29) 45 As a result of evidence that Pb in paint could cause neurological deficits when ingested by children, Pb was removed from paint in Europe in 1922 and in the United States in 1978.(30,31) However, banning the sale of leaded paint did not remove the 50 threat of Pb contamination in homes already containing leaded paint. Many homes in the United States still contain leaded paint,(31,32) especially in city centers.(33) Chipped and peeling leaded paint 25
2 | Journal Name, [year], [vol], 00–00
constitutes a major source of current childhood Pb 55 exposure, as the desiccated paint can easily disintegrate at friction surfaces to form Pb dust.(34,35) Pb dust can also be formed from the combustion of leaded fuels; previous emissions of leaded fuel resulted in a massive dispersion of Pb dust in the 60 environment, especially along roadways.(36) Particulate Pb is characteristically fine (2-10 µm),(36) does not degrade, and continues to be a major source of human exposure.(33,37) Drinking water can be another source of 65 environmental Pb exposure. Leaching of Pb into drinking water occurs from outdated fixtures and solders containing Pb. The significance of Pb leaching into drinking water was emphasized during the 2001 Washington, DC, “Lead in drinking water 70 crisis,” when leaching of Pb from pipes into drinking water rapidly increased the amount of Pb contamination, resulting in a 9.6 fold increase in the incidence of elevated blood Pb levels in children.(38) This unfortunate incident highlights the role 75 contaminated drinking water can play in overall childhood Pb exposure. The current action level for Pb in water has been set at 15 ppb (15 µg/L) by the United States Environmental Protection Agency (EPA). Although the majority of water suppliers in 80 the United States are in compliance with this action level, children can still be exposed to Pb levels higher than 15 ppb (15 µg/L) if the plumbing contains leaded components that do not have optimized corrosion control. Without optimized corrosion 85 control systems, Pb can leach into drinking water from leaded plumbing components. Furthermore, not all water systems are subject to EPA regulation; for example, well water is not subject to the 15 ppb (15 µg/L) action level and is not routinely tested for Pb 90 levels. It is estimated that up to 45 million people in the United States drink water that is not subject to EPA regulations. The Pb exposure from drinking water remain unknown in these water systems.(39) Due to the success of environmental 95 interventions regarding Pb, childhood Pb exposure in the US has decreased since the 1970’s. The most recent evidence indicates that contemporary childhood BLLs in the US are on the order of 1.9 µg/dL while the percentage of children with elevated (27) 100 BLLs (above 10 µg/dL) has dropped to 1.4%. Peak BLLs occur when children are roughly 2 years of age.(14,17,40,41) Significant decreases in BLLs have been observed in this age group as well: average BLLs have decreased to 2.1 µg/dL and the percentage of 105 children in this age group with elevated BLLs dropped to 2.4%.(27) Thus, the contemporary exposure This journal is © The Royal Society of Chemistry [year]
Toxicology Research Accepted Manuscript
View Article Online
result in distinct neurological effects, with different brain targets and modes of action, they share a key similarity in that they both disrupt synaptic transmission. The aims of this review are to 5 summarize the toxicokinetics of Pb and Mn, describe their neurotoxic mechanisms, and discuss common themes in their neurotoxicity.
Page 3 of 17
Toxicology Research
Downloaded on 08 January 2013 Published on 03 January 2013 on http://pubs.rsc.org | doi:10.1039/C2TX20064C
Pb Toxicokinetics
The main routes of exposure for Pb are inhalation and ingestion. Inhalation exposure to Pb is a much more 15 efficient route of absorption than ingestion, with an estimated absorption efficiency ratio of 10 to 1 in the lung compared to the GI tract.(43,44) Due to the reduction in use of leaded gasoline, inhalation exposure in developed countries is generally limited 20 to people who live near smelters and to workers in occupational settings.(45,46) Pb can adsorb onto particulate matter (PM) and thus be inhaled. Inhalation studies classify PM by size; PM10 contains PM of aerodynamic diameter ≤ 10 µm, while 25 PM2.5 contains PM of aerodynamic diameter ≤2.5 µm.The deposition of inhaled inorganic Pb is dependent on particle size and composition. Particles >2.5 µm are deposited in the upper airways and can be cleared via mucociliary clearance. Particles
