Resolving scientific controversy over smelter risks and neurodegenerative effects of metals

Rebecca L. Thomas; Kristin S. Shrader-Frechette; Rebecca L. Thomas; Kristin S. Shrader-Frechette

doi:10.3934/environsci.2015.1.56

AIMS Environmental Science

2015, Volume 2, Issue 1: 56-86. doi: 10.3934/environsci.2015.1.56

Previous Article Next Article

Review

Resolving scientific controversy over smelter risks and neurodegenerative effects of metals

Rebecca L. Thomas ¹,
Kristin S. Shrader-Frechette ^{2
,
,}

1.
Environmental Sciences Department, University of Notre Dame, Notre Dame, IN, USA 46556;
2.
Biological Sciences Department and Philosophy Department, 100 Malloy Hall, University of Notre Dame, Notre Dame, IN, USA 46556

Received: 01 February 2014 Accepted: 06 February 2015 Published: 15 February 2015

Although it is well known that metals pollution can cause neurotoxic effects, scientists are currently divided about the neurodegeneration hypothesis. That is, some scientists accept, while others fail to accept, the hypothesis that metals/metalloids, at exposure levels below those capable of causing neurotoxicity, can cause neurodegeneration—progressive or worsening neurological disease. Partly because of controversy over the neurodegeneration hypothesis, the US and other governments do not require cleanup of smelter-site metals, to the level (that many scientists say is) necessary to prevent site-caused neurodegenerative disease. The purpose of this review article is to help clarify and resolve conflict over the neurodegeneration hypothesis. This analysis (1) surveys the global problem of smelter-related metals pollution; (2) quickly gives an overview of metals pollution at one of the worst US Superfund or hazardous-waste sites, a former smelter in DePue, Illinois; (3) outlines the debate over the neurodegeneration hypothesis; and (4) assesses the current science on both sides of the neurodegeneration hypothesis by means of three classic methods of causal assessment: the mechanism, unification-coherence, and experimental-counterfactual methods. Using these classic methods, the authors (5) show that available scientific evidence argues for accepting the neurodegeneration hypothesis. This finding is significant because it suggests that much current science about smelters and metals' risks may be incomplete or flawed. It also shows that, as a result, there may be sound scientific reasons for strengthening environmental-metals standards.
- cause,
- coherence,
- mechanism,
- metal,
- neurobiology,
- neurodegeneration,
- neurotoxicity,
- smelter,
- unification
Citation: Rebecca L. Thomas, Kristin S. Shrader-Frechette. Resolving scientific controversy over smelter risks and neurodegenerative effects of metals[J]. AIMS Environmental Science, 2015, 2(1): 56-86. doi: 10.3934/environsci.2015.1.56

Related Papers:

Abstract

Although it is well known that metals pollution can cause neurotoxic effects, scientists are currently divided about the neurodegeneration hypothesis. That is, some scientists accept, while others fail to accept, the hypothesis that metals/metalloids, at exposure levels below those capable of causing neurotoxicity, can cause neurodegeneration—progressive or worsening neurological disease. Partly because of controversy over the neurodegeneration hypothesis, the US and other governments do not require cleanup of smelter-site metals, to the level (that many scientists say is) necessary to prevent site-caused neurodegenerative disease. The purpose of this review article is to help clarify and resolve conflict over the neurodegeneration hypothesis. This analysis (1) surveys the global problem of smelter-related metals pollution; (2) quickly gives an overview of metals pollution at one of the worst US Superfund or hazardous-waste sites, a former smelter in DePue, Illinois; (3) outlines the debate over the neurodegeneration hypothesis; and (4) assesses the current science on both sides of the neurodegeneration hypothesis by means of three classic methods of causal assessment: the mechanism, unification-coherence, and experimental-counterfactual methods. Using these classic methods, the authors (5) show that available scientific evidence argues for accepting the neurodegeneration hypothesis. This finding is significant because it suggests that much current science about smelters and metals' risks may be incomplete or flawed. It also shows that, as a result, there may be sound scientific reasons for strengthening environmental-metals standards.

References

[1]	US Congress, House of Representatives: Poison Harvest. Government Printing Office, Washington, D.C, 2012. Available from: http: //www.gpo.gov/fdsys/pkg/CHRG-112hhrg75164/html/CHRG-112hhrg75164.htm.
[2]	Kabir E, Sharmila R, Kim K, et al. (2012) Current Status of Trace Metal Pollution in Soils Affected by Industrial Activities. Sci World J 2012: 1-18.
[3]	Grandjean P, Landrigan PJ (2014) Neurobehavioural Effects of Developmental Toxicity. Lancet Neurol 13: 330-338. doi: 10.1016/S1474-4422(13)70278-3
[4]	Centeno JA, Tseng CH, Van der Voet GB, et al. (2007) Global impacts of geogenic arsenic. Ambio 36: 78-81. doi: 10.1579/0044-7447(2007)36[78:GIOGAA]2.0.CO;2
[5]	Hu H, Shine J, Wright RO (2007) The challenge posed to children's health by mixtures of toxic waste. Pediatr Clin N Am 54: 155-174. doi: 10.1016/j.pcl.2006.11.009
[6]	Eckel WP, Rabinowitz MB, Foster GD (2011) Discovering unrecognized lead-smelting sites by historical methods. Am J Public Health 91: 625-627.
[7]	Zota AR, Schaider LA, Ettinger AS, et al. (2011) Metal sources and exposures in the homes of young children living near a mining-impacted Superfund site. J Expo Sci Environ Epidemiol 21: 495-505. doi: 10.1038/jes.2011.21
[8]	Falco C (2013) Response to Village re: December 20, 2012 Comments. Illinois EPA, Springfield
[9]	Environ International Corporation (2012). Off-Site Soils Design Study. OU4: Off-Site Soils, DePue Site, De Pue, Illinois: Environ International Corporation, On behalf of The DePue Group. Project No. 21-2046C. March 2012.
[10]	California Office of Environmental Health Hazards Assessment (COEHHA). (2009) Review Draft Revised California Human Health Screening Level for Lead. Sacramento, California: COEHHA; Available from: http: //oehha.ca.gov/risk/chhsl051809.html.
[11]	Schiffer RB, McDermott MP, Copley C (2001) A multiple-sclerosis cluster associated with a small, north central Illinois community. Arch Environ Health 56: 389-395. doi: 10.1080/00039890109604473
[12]	Acosta-Saavedra LC, Ma EM, Rodriguez-Kessler T, et al. (2011) Environmental exposure to lead and mercury in Mexican children. Toxicol Mech Methods 21: 656-666. doi: 10.3109/15376516.2011.620997
[13]	Bar-Sela S, Reingold S, Richter ED (2001) Amyotrophic lateral sclerosis in a battery factory worker exposed to cadmium. Int J Occup Med Environ Health 7: 109-112. doi: 10.1179/oeh.2001.7.2.109
[14]	Braun JM, Kahn RS, Froehlich T, et al. (2006) Exposures to environmental toxicants and attention deficit hyperactivity disorder in US children. Environ Health Persp 114: 1904-1909.
[15]	Chasapis C, Loutsidou AC, Spiliopoulou CA, et al. (2012) Zinc and human health: an update. Arch Toxicol 86: 521-534. doi: 10.1007/s00204-011-0775-1
[16]	Chen L, Xu B, Liu L, et al. (2011) Cadmium induction of reactive oxygen species activates the mTOR pathway, leading to neuronal cell death. Free Radical Bio Med 50: 624-632. doi: 10.1016/j.freeradbiomed.2010.12.032
[17]	Choi BY, Jang BG, Kim JH, et al. (2013) Copper/zinc chelation by clioquinol reduces spinal cord white matter damage and behavioral deficits in a murine MOG-induced multiple sclerosis model. Neurobiol Dis 54: 382-391. doi: 10.1016/j.nbd.2013.01.012
[18]	Farina M, Avila DS, da Rocha JBT, et al. (2013) Metals, oxidative stress and neurodegeneration. Neurochem Int 62: 575-594. doi: 10.1016/j.neuint.2012.12.006
[19]	Gong G, O'Bryant SE (2010) The arsenic exposure hypothesis for Alzheimer disease. Alzheimer Dis Assoc Disord, 24: 311-316. doi: 10.1097/WAD.0b013e3181d71bc7
[20]	Gu H, Wei X, Monnot AD, et al. (2011) Lead exposure increases levels of beta-amyloid in the brain and CSF and inhibits LRP1 expression in APP transgenic mice. Neurosci Lett 490: 16-20. doi: 10.1016/j.neulet.2010.12.017
[21]	Gu H, Robinson G, Hong L, et al. (2012) Increased β amyloid deposition in Tg-SWDI transgenic mouse brain following in vivo lead exposure. Toxicol Lett 213: 211-219. doi: 10.1016/j.toxlet.2012.07.002
[22]	Guilarte T (2010) APLP1, Alzheimer's-like pathology and neurodegeneration in the frontal cortex of manganese exposed non-human primates. Neurotoxicology 31: 572-574. doi: 10.1016/j.neuro.2010.02.004
[23]	Kim EA, Kang SK (2010) Occupational neurological disorders in Korea. J Korean Med Soc 25: S26-S35. doi: 10.3346/jkms.2010.25.S.S26
[24]	Lanphear BP, Hornung R, Khoury J, et al. (2005) Low-level environmental lead exposure and children's intellectual function. Environ Health Persp 113: 894-899. doi: 10.1289/ehp.7688
[25]	Lassmann H, van Horssen J, Mahad D (2012) Progressive multiple sclerosis. Nat Rev Neurol 8: 647-656. doi: 10.1038/nrneurol.2012.168
[26]	LeVine SM, Bilgin M, Lynch SG (2013) Iron accumulation in multiple sclerosis. Expert Rev Neurother 13: 247-250. doi: 10.1586/ern.13.14
[27]	Mates JM, Segura JA, Alonso FJ, et al. (2010) Roles of dioxins and heavy metals in cancer and neurological diseases using ROS-mediated mechanisms. Free Radical Bio Med 49: 1328-1341. doi: 10.1016/j.freeradbiomed.2010.07.028
[28]	Mazumdar M, Xia W, Hofmann O, et al. (2012) Prenatal lead levels, plasma amyloid beta levels, and gene expression in young adulthood. Environ Health Persp 120: 702-707. doi: 10.1289/ehp.1104474
[29]	Olopade JO, Ponnuru P, Connor JR (2010). Erythropoietin, desferroxamine and iron are protective against vanadium-induced demyelination and oxidative stress in the rat brain Neurotoxicology 31: 582-588.
[30]	Sharma B, Sharma PM (2013) Arsenic toxicity induced endothelial dysfunction and dementia. Toxicol Appl Pharm 273: 180-188. doi: 10.1016/j.taap.2013.07.017
[31]	Squitti R, Polimanti R, Siotto M, et al. (2013) ATP7B variants as modulators of copper dyshomeostasis in Alzheimer's Disease. NeuroMol Med 15: 515-522. doi: 10.1007/s12017-013-8237-y
[32]	Suzuki Y, Inoue T, Ra C (2011) Autoimmunity-inducing metals (hg, au, and ag) modulate mast cell signaling, function, and survival. Curr Pharm Design 17: 3805-3814. doi: 10.2174/138161211798357917
[33]	Taba P (2013) Metals and movement disorders. Curr Opin Neurol 26: 435-441. doi: 10.1097/WCO.0b013e3283629beb
[34]	Tsai CP, Lee CTC (2013) Multiple sclerosis incidence associated with the soil lead and arsenic concentrations in Taiwan. PLoS One 8: 1-6.
[35]	Urrutia P, Aguirre P, Esparza A, et al. (2013) Inflammation alters the expression of DMT1, FPN1 and hepcidin, and it causes iron accumulation in central nervous system cells. J Neurochem 126: 541-549. doi: 10.1111/jnc.12244
[36]	Valera P, Zavattari P, Albanese S, et al. (2013) A correlation study between multiple sclerosis and type 1 diabetes incidences and geochemical data in Europe. Environ Geochem Hlth 10: 79-98.
[37]	Verina T, Schneider JS, Guilarte TR (2013) Manganese exposure induces alpha-synuclein aggregation in the frontal cortex of non-human primates. Toxicol Lett 217: 177-183. doi: 10.1016/j.toxlet.2012.12.006
[38]	Vitvitsky VM, Sanjay K, Garg K, et al. (2012) Na+ and K+ ion imbalances in Alzheimer's disease. Biochim Biophys Acta 1822: 1671-1681. doi: 10.1016/j.bbadis.2012.07.004
[39]	Wang JD, Huang CC, Hwang YH, et al. (1989) Manganese induced Parkinsonism. Brit J Ind Med 46: 856-859.
[40]	Yorifuji T, Debes F, Weihe P, et al. (2011) Prenatal exposure to lead and cognitive deficit in 7- and 14-year old children in the presence of concomitant exposure to similar molar concentration of methylmercury. Neurotoxicol Teratol 33: 205-211. doi: 10.1016/j.ntt.2010.09.004
[41]	Pan-Montojo P, Reichmann H (2014) Considerations on the role of environmental toxins in idiopathic Parkinson's disease pathophysiology. Transl Neurodegener 3: 10. doi: 10.1186/2047-9158-3-10
[42]	El-Fawal HAN (2014) Neuroantibody biomarkers. Autoimmune Dis 2014: 1-12.
[43]	Lahiri DK, Maloney B Zawia NH (2009) The LEARn model. Mol Psychiatr 14: 992-1003. doi: 10.1038/mp.2009.82
[44]	World Health Organization (WHO) (2006) Neurological Disorders. World Health Organization, Geneva.
[45]	Choo XY, Alukaidey L, White AR, et al. (2013) Neuroinflammation and copper in Alzheimer's disease. Int J Alzheimers Dis 13: 1-12.
[46]	Rosen C, Hansson O, Blennow K, et al. (2013) Fluid biomarkers in Alzheimer's disease: current concepts. Mol Neurodegener 8: 20. doi: 10.1186/1750-1326-8-20
[47]	Thompson LM (2008) Neurodegeneration: a question of balance. Nature 452: 707-708. doi: 10.1038/452707a
[48]	Rubinsztein DC (2006) The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443: 780-6. doi: 10.1038/nature05291
[49]	Bredesen DE, Rao RV, Mehlen P (2006) Cell death in the nervous system. Nature 443: 796-802. doi: 10.1038/nature05293
[50]	Calderon-Garcideuenas L, Serrano-Sierra A, Torres-Jardon R, et al. (2013) The impact of environmental metals in young urbanites' brains. Exp Toxicol Pathol 65: 503-511. doi: 10.1016/j.etp.2012.02.006
[51]	Csavina J, Field J, Taylor MP, et al. (2012) A review on the importance of metals and metalloids in atmospheric dust and aerosol from mining operations. Sci Total Environ 433: 58-73. doi: 10.1016/j.scitotenv.2012.06.013
[52]	Mutter J, Curth A, Naumann J, et al. (2010) Does inorganic mercury play a role in Alzheimer's disease? A systematic review and an integrated molecular mechanism. J Alzheimers Dis 22: 357-374.
[53]	Beyersmann D (2002) Effects of carcinogenic metals on gene expression. Toxicol Lett 127(1): 63-68.
[54]	Calabrese EJ, Baldwin LA (2003) Toxicology rethinks its central belief. Nature 421: 691-692. doi: 10.1038/421691a
[55]	Cook R, Calabrese EJ (2006) The importance of hormesis to public health. Environ Health Persp 114: 1631-1635.
[56]	Fukushima S, Kinoshita A, Puatanachokchai R, et al. (2005) Hormesis and dose–response-mediated mechanisms in carcinogenesis. Carcinogenesis 26: 1835-1845. doi: 10.1093/carcin/bgi160
[57]	Jiang G, Duan W, Xu L, et al. (2009) Biphasic effect of cadmium on cell proliferation in human embryo lung fibroblast cells and its molecular mechanism. Toxicol in Vitro 23: 973-978. doi: 10.1016/j.tiv.2009.06.029
[58]	Lefcort H, Freedman Z, House S, et al. (2008) Hormetic effects of heavy metals in aquatic snails. EcoHealth 5: 10-17. doi: 10.1007/s10393-008-0158-0
[59]	Schmidt CM (2004) Hormesis effect of trace metals on cultured normal and immortal human mammary cells. Toxicol Ind Health 201: 57-68.
[60]	Sandstead HH (1986) A brief history of the influence of trace elements on brain function. Am J Clin Nutr 43: 293-298.
[61]	Fraga CG (2005) Relevance, essentiality and toxicity of trace elements in human health. Mol Aspects Med 26: 235-244. doi: 10.1016/j.mam.2005.07.013
[62]	Leblanc JC, Guérin T, Noël L, et al. (2005) Dietary exposure estimates of 18 elements from the 1st French total diet study. Food Addit Contam 22: 624-641. doi: 10.1080/02652030500135367
[63]	Duruibe JO, Ogwuegbu MOC, Egwurugwu JN (2007) Heavy metal pollution and human biotoxic effects. Int J Phys Sci 2: 112-118.
[64]	Rainbow PS (2002) Trace metal concentrations in aquatic invertebrates. Environ Pollut 120: 497-507. doi: 10.1016/S0269-7491(02)00238-5
[65]	Silvera SAN, Rohan TE (2007) Trace elements and cancer risk. Cancer Cause Control 18: 7-27. doi: 10.1007/s10552-006-0057-z
[66]	Jomova K, Valko M (2011) Advances in metal-induced oxidative stress and human disease. Toxicology 283: 65-87. doi: 10.1016/j.tox.2011.03.001
[67]	Agency for Toxic Substances and Disease Registry: Toxicological Profile for Cobalt. US Department of Health and Human Services, 2004. Available from: http://www.atsdr.cdc.gov.proxy.library.nd.edu/toxprofiles/tp33.pdf.
[68]	Trumbo P, Yates AA, Schliker S, et al. (2001) Dietary reference intakes. J Am Diet Assoc 101: 294-301. doi: 10.1016/S0002-8223(01)00078-5
[69]	Moulton PV, Yang W (2012) Air Pollution, Oxidative Stress, and Alzheimer's Disease. J Environ Public Health 2012: 1-9.
[70]	Rockers PC, Feigla AB, Røttingen J, et al. (2012) Study-design selection criteria in systematic reviews of effectiveness of health systems interventions and reforms: A meta-review. Health Policy 104: 206-214. doi: 10.1016/j.healthpol.2011.12.007
[71]	Moher D, Liberati AL, Tetzlaff J, et al. (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62: 1006-1012. doi: 10.1016/j.jclinepi.2009.06.005
[72]	Khan KS, Kunz R, Kleijnen J, et al. (2003) Five steps to conducting a systematic review. J R Soc Med 96: 118-121. doi: 10.1258/jrsm.96.3.118
[73]	Environmental Protection Agency (EPA): Guidelines for carcinogen risk assessment. Washington, DC Risk Assessment Forum, 2005. Available from: http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2010-0877-0021, 2-11.
[74]	Environmental Protection Agency (EPA): Endocrine disruptor screening program, weight-of-evidence. Washington, DC, 2011. Available from: http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2010-0877-0021, 28.
[75]	Hill AB (1965) The environment and disease. P Roy Soc Med 58: 295-300.
[76]	Swaen G, van Amelsvoort L (2009) A weight-of-evidence approach to causal inference. J Clin Epidemiol 62: 270-277. doi: 10.1016/j.jclinepi.2008.06.013
[77]	International Agency for Research on Cancer (IARC): IARC monographs on the evaluation of carcinogenic risks to humans. World Health Organization, 2014. Available from: http://monographs.iarc.fr/ENG/Classification/.
[78]	Phillips CV, Goodman KJ (2004) The missed lessons of Sir Austin Bradford Hill. Epidemiol Perspect Innov 1: 3. doi: 10.1186/1742-5573-1-3
[79]	Institute of Medicine (IOM) Committee on Understanding Premature Birth and Assuring Healthy Outcomes; Behrman RE, Butler AS, editors (2007) Preterm birth: causes, consequences, and prevention. Washington DC: National Academies Press.
[80]	Machamer P, Darden L, Craver CF (2000) Thinking about mechanisms. Philos Sci 67: 1-25. doi: 10.1086/392759
[81]	Glennan S (2002) Rethinking mechanistic explanation. Philos Sci 69: S342-S353. doi: 10.1086/341857
[82]	Craver CF (2006) When mechanistic models explain. Synthese 153: 355-376. doi: 10.1007/s11229-006-9097-x
[83]	Campaner R (2011) Mechanistic causality and counterfactual-manipulative causality. J Epidemiol Commun H 65: 1070-1074. doi: 10.1136/jech.2011.134205
[84]	Brigandt I (2013) Systems biology and the integration of mechanistic explanation and mathematical explanation. Stud Hist Philos Sci C 44: 477-492.
[85]	Garson J (2013) The functional sense of mechanism. Philos Sci 80: 317-333. doi: 10.1086/671173
[86]	Howick J (2011) Exposing the vanities—and a qualified defense—of mechanistic reasoning in health care decision making. Philos Sci 78: 926-940. doi: 10.1086/662561
[87]	Leuridan B (2014) The structure of scientific theories, explanation, and unification. A causal–structural account. Br J Philos Sci 65: 717-771. doi: 10.1093/bjps/axt015
[88]	Thagard P (2003) Pathways to biomedical discovery. Philos Sci 70: 235-254. doi: 10.1086/375465
[89]	Baetu TM (2012) Genomic Programs as Mechanism Schemas: A Non-Reductionist Interpretation. Brit J Philos Sci 63: 649-671. doi: 10.1093/bjps/axr042
[90]	Darden L (2008) Thinking again about biological mechanisms. Philos Sci 75: 958-969. doi: 10.1086/594538
[91]	Salmon WC (1989) Four Decades of Scientific Explanation. Minneapolis: University of Minnesota Press.
[92]	Feigl H (1970) The ‘Orthodox' View of Theories. In M. Radner and S. Winokur (eds), Minnesota Studies in the Philosophy of Science, Volume IV. Minneapolis: University of Minnesota Press.
[93]	Freiman JA, Chalmers TC, Smith H, et al. (1978) The importance of beta, the type II error and sample size in the design and interpretation of the randomized control trial. N Engl J Med 299: 690-694. doi: 10.1056/NEJM197809282991304
[94]	Plutynski A (2005) Explanatory unification and the early synthesis. Brit J Philos Sci 56: 595-609. doi: 10.1093/bjps/axi124
[95]	Cat J (1998) The physicists' debates on unification in physics at the end of the 20th century. Hist Stud Phys Biol 28: 253-299. doi: 10.2307/27757796
[96]	Nathan MJ (2012) The Varieties of Molecular Explanation. Philos Sci 79: 233-254. doi: 10.1086/664791
[97]	Van Fraassen B (1980) The Scientific Image. New York: Oxford University Press.
[98]	Cartwright N (1983) How the Laws of Physics Lie. New York: Oxford University Press.
[99]	Woodward J (2003) Making Things Happen: A Theory of Causal Explanation. New York: Oxford University Press, 11.
[100]	Waters CK (2007) Causes that Make a Difference. J Philos 104: 551-579.
[101]	Eberhardt F, Scheines R (2007) Interventions and causal inference. Philos Sci 74: 981-995. doi: 10.1086/525638
[102]	Bokulich A (2012) Distinguishing explanatory from nonexplanatory fictions. Philos Sci 79: 725-737. doi: 10.1086/667991
[103]	Goodwin W (2013) Quantum Chemistry and Organic Theory. Philos Sci 80: 1159-1169. doi: 10.1086/673734
[104]	Loeb N (2012) Letter of December 17, 2012 to EPA DePue Superfund Site Project Director. Bluhm Legal Clinic, Northwestern Law School.
[105]	US EPA (2010) Framework for Incorporating Human Epidemiologic and Incident Data in Health Risk Assessment. Risk Assessment Forum, Office of Pesticides Programs, U.S. Environmental Protection Agency.
[106]	Ou-Yan MH, Van Nostrand WE (2013) The absence of myelin basic protein promotes neuroinflammation and reduces amyloid B-protein accumulation in Tg-5xFAD mice. J Neuroinflammation 10: 134. doi: 10.1186/1742-2094-10-134
[107]	Butterfield DA, Reed T, Newman SF, et al. (2007) Roles of amyloid β-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer's disease and mild cognitive impairment. Free Radical Bio Med 43: 658-677. doi: 10.1016/j.freeradbiomed.2007.05.037
[108]	Forster MJ, Dubey A, Dawson KM, et al. (1996) Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain. P Natl Acad Sci USA 93: 4765-4769. doi: 10.1073/pnas.93.10.4765
[109]	Carney JM, Starke-Reed PE, Oliver CN, et al. (1991) Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone. P Natl Acad Sci USA 88: 3633-3636. doi: 10.1073/pnas.88.9.3633
[110]	Ayton S, Lei P, Bush AI (2013) Metallostasis in Alzheimer's disease. Free Radical Bio Med 62: 76-89. doi: 10.1016/j.freeradbiomed.2012.10.558
[111]	Faller P, Hureau C, Berthoumieu O (2013) Role of metal ions in the self-assembly of the Alzheimer's amyloid-β peptide. Inorg Chem 52: 12193-12206. doi: 10.1021/ic4003059
[112]	Greenough MA, Camakaris J, Bush AI (2013) Metal dyshomeostasis and oxidative stress in Alzheimer's disease. Neurochem Int 62: 540-555. doi: 10.1016/j.neuint.2012.08.014
[113]	Jellinger KA (2013) The relevance of metals in the pathophysiology of neurodegeneration, pathological considerations. In International Review of Neurobiology, ed Bhatia KP and Schneider SA, Elsevier, Oxford, 1-48.
[114]	Myhre O, Utkilen H, Duale N, et al. (2013) Metal dyshomeostasis and inflammation in Alzheimer's and Parkinson's diseases. Oxid Med Cell Longev 2013: 1-19.
[115]	Obulesu M, Jhansilakshmi M (2014) Neuroinflammation in Alzheimer's disease. Int J Neurosci 124: 227-235. doi: 10.3109/00207454.2013.831852
[116]	Urrutia P, Mena NP, Nunez MT (2014) The interplay between iron accumulation, mitochondrial dysfunction, and inflammation during the execution step of neurodegenerative disorders. Front Pharmacol 38: 1-12.
[117]	Xu PX, Wang SW, Yu XL, et al. (2014) Rutin improves spatial memory in Alzheimer's disease transgenic mice by reducing AB oligomer level and attenuating oxidative stress and neuroinflammation. Behav Brain Res 264: 173-180. doi: 10.1016/j.bbr.2014.02.002
[118]	Zhang W, Yan ZF, Gao JH, et al. (2013) Role and mechanism of microglial activation in iron-induced selective and progressive dopaminergic neurodegeneration. Mol Neurobiol 10: 1-13.
[119]	Nolan YM, Sullivan AM, Toulouse A (2013) Parkinson's disease in the nuclear age of neuroinflammation. Trends Mol Med 19: 187-196. doi: 10.1016/j.molmed.2012.12.003
[120]	Attar AM, Kharkhaneh A, Etemadifar M, et al. (2012) Serum mercury level and multiple sclerosis. Biol Trace Elem Res 146: 150-153. doi: 10.1007/s12011-011-9239-y
[121]	Hozumi I, Hasegawa T, Honda A, et al. (2011) Patterns of levels of biological metals in CSF differ among neurodegenerative diseases. J Neurol Sci 303: 95-99. doi: 10.1016/j.jns.2011.01.003
[122]	Gu H, Wei X, Monnot AD, et al. (2011) Lead exposure increases levels of beta-amyloid in the brain and CSF and inhibits LRP1 expression in APP transgenic mice. Neurosci Lett 490: 16-20. doi: 10.1016/j.neulet.2010.12.017
[123]	Losy J (2013) Is MS an inflammatory or primary degenerative disease? J Neural Transm 120: 1459-1462. doi: 10.1007/s00702-013-1079-9
[124]	Brown GC and Neher JJ (2010) Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Mol Neurobiol 41: 242-247. doi: 10.1007/s12035-010-8105-9
[125]	Serhan CN, Ward PA, Gilroy DW (2010) Acute and chronic inflammation. Fund Inflamm 2010: 1-16.
[126]	Walsh S, Finn DP, Dowd E (2011) Time-course of nigrostriatal neurodegeneration and neuroinflammation in the 6-hydroxydopamine-induced axonal and terminal lesion models of Parkinson's disease in the rat. Neuroscience 175: 251-261. doi: 10.1016/j.neuroscience.2010.12.005
[127]	Becaria A, Lahiri DK, Bondy SC, et al. (2006) Aluminum and copper in drinking water enhance inflammatory or oxidative events specifically in the brain. J Neuroimmunol 176: 16-23. doi: 10.1016/j.jneuroim.2006.03.025
[128]	Reinardy HC, Syrett JR, Jeffree RA, et al. (2013) Cobalt-induced genotoxicity in male zebrafish. Aquat Toxicol 126: 224-230. doi: 10.1016/j.aquatox.2012.11.007
[129]	Roos P M, Vesterberg O, Syversen T, et al. (2013) Metal concentrations in cerebrospinal fluid and blood plasma from patients with amyotrophic lateral sclerosis. Biol Trace Elem Res 151: 159-170. doi: 10.1007/s12011-012-9547-x
[130]	Paling D, Solanky BS, Riemer F, et al. (2013) Sodium accumulation is associated with disability and a progressive course in multiple sclerosis. Brain 136: 2305-2317 doi: 10.1093/brain/awt149
[131]	Klien K and Godnić-Cvar J (2012) Genotoxicity of metal nanoparticles. Arh Hig Rada Toksikol 63: 133-145.
[132]	Ferreira PC, Kde P, Takayanagui AM, et al. (2008) Aluminum as a risk factor for Alzheimer's disease. Rev Lat Am Enfermagem 16: 151-157. doi: 10.1590/S0104-11692008000100023
[133]	Gillette-Guyonnet S, Andrieu S, Nourhashemi F, et al. (2005) Cognitive impairment and composition of drinking water in women. Am J Clin Nutr 81: 897-902.
[134]	McLachlan DR, Bergeron C, Smith JE, et al. (1996) Risk for neuropathologically confirmed Alzheimer's disease and residual aluminum in municipal drinking water. Neurology 46: 401-405. doi: 10.1212/WNL.46.2.401
[135]	Forster DP, Newens AJ, Kay DW, et al. (1995) Risk factors in clinically diagnosed presenile dementia of the Alzheimer type. J Epidemiol Community Health 49: 253-258 doi: 10.1136/jech.49.3.253
[136]	Burns CJ, McIntosh LJ, Mink PJ, et al. (2013) Pesticide Exposure and Neurodevelopmental Outcomes: Review of the Epidemiologic and Animal Studies. J Toxicol Env Heal B 16: 127-283. doi: 10.1080/10937404.2013.783383
[137]	US Environmental Protection Agency (US-EPA): National Priorities List. US-EPA, 2012. Available from: http: //www.epa.gov/superfund/sites/query/queryhtm/nplfin2.htm.
[138]	Gwiazda R, Lucchini R, Smith D (2007) Adequacy and consistency of animal studies to evaluate the neurotoxicity of chronic low-level manganese exposure in humans. J Toxicol Environ Health 70: 594-605. doi: 10.1080/10937400600882897
[139]	Hackam DG, Redelmeier DA (2006) Translation of research evidence from animals to humans. JAMA 296: 1727-1732.
[140]	Apostoli P, Kiss P, Porru S, et al. (1998) Male reproductive toxicity of lead in animals and humans. Occup Environ Med 55: 364-374. doi: 10.1136/oem.55.6.364
[141]	Alarie, Y (1981) Dose-response analysis in animal studies. Environ Health Persp 42: 9-13. doi: 10.1289/ehp.81429
[142]	Olson H, Betton G, Robinson D, et al. (2000) Concordance of the toxicity of pharmaceuticals in humans and in animals. Regul Toxicol Pharm 32: 56-67. doi: 10.1006/rtph.2000.1399
[143]	Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22: 659-661.
[144]	Shrader-Frechette KS (2008) Evidentiary standards and animal data. Environ Justice 1: 139-144. doi: 10.1089/env.2008.0528
[145]	Willis AW, Evanoff BA, Lian M, et al. (2010) Metal emissions and urban incident Parkinson Disease. Am J Epidemiol 172: 1357-1363. doi: 10.1093/aje/kwq303
[146]	Racette BA, McGee-Minnich L, Moerlei SM, et al. (2001) Welding-related parkinsonism. Neurology 56: 8-13. doi: 10.1212/WNL.56.1.8
[147]	Bar-Sela S, Levy M, Westin JB, et al. (1992) Medical findings in nickel-cadmium battery workers. Israel J Med Sci 28: 578-583.
[148]	Miura N (2009) Individual susceptibility to cadmium toxicity and metallothionein gene polymorphisms: with references to current status of occupational cadmium exposure. Ind Health 47: 487-494. doi: 10.2486/indhealth.47.487
[149]	Bellinger DC (2012) A strategy for comparing the contributions of environmental chemicals and other risk factors to neurodevelopment of children. Environ Health Persp 120: 501-507.
[150]	Sanders AP, Miller SK, Nguyen V, et al. (2014) Toxic metal levels in children residing in a smelting-craft village in Vietnam. BMC Pub Health 14: 114. doi: 10.1186/1471-2458-14-114
[151]	Stein J, Schettler T, Wallinga D, et al. (2002) In harm's way. J Dev Behav Pediatr 23: S13-S22. doi: 10.1097/00004703-200202001-00004
[152]	Mann JM (1997) Medicine and public health, ethics and human rights. The Hastings Center Report 27: 6-13.
[153]	Rosenbaum PR (2010) Design of Observational Studies. Springer, New York
[154]	Kitcher P (1989) Explanatory unification and the causal structure of the world. Sci Explan 13: 410-505.
[155]	Sears ME (2013) Chelation: Harnessing and Enhancing Heavy Metal Detoxification—A Review. ScientificWorldJournal 2013: 1-13.
[156]	Ward RJ, Dexter DT, Crichton RR (2012) Chelating agents for neurodegenerative diseases. Curr Med Chem 19: 2760-2772. doi: 10.2174/092986712800609689
[157]	Bolognin S, Drago D, Messori L, et al. (2009) Chelation therapy for neurodegenerative diseases. Med Res Rev 29: 547-570. doi: 10.1002/med.20148
[158]	Dang TNT, Lim NKH, Grubman A, et al. (2014) Increased metal content in the TDP-43A315T transgenic mouse model of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Front Aging Neurosci 6: 15-34.
[159]	Grubman A, White AR, Liddell JR (2014) Mitochondrial metals as a potential therapeutic target in neurodegeneration. Brit J Pharmacol 171: 2159-2173. doi: 10.1111/bph.12513
[160]	Stephenson E, Nathoo N, Mahjoub Y, et al. (2014) Iron in multiple sclerosis: roles in neurodegeneration and repair. Nat Rev Neurol 10: 459-468. doi: 10.1038/nrneurol.2014.118
[161]	Kanninen KM, Grubman A, Meyerowitz J, et al. (2013) Increased Zinc and Manganese in Parallel with Neurodegeneration, Synaptic Protein Changes and Activation of Akt/GSK3 Signaling in Ovine CLN6 Neuronal Ceroid Lipofuscinosis. PLOS One 8.
[162]	Mitchell SD (2000) Dimensions of Scientific Law. Philos Sci 67: 242-265. doi: 10.1086/392774
[163]	Weber M (2006) The central dogma as a thesis of causal specificity. Hist Phil Life Sci 28: 595-609.
[164]	Hitchcock C (2007) Prevention, preemption, and the principle of sufficient reason. Phil Review 116: 495-532. doi: 10.1215/00318108-2007-012
[165]	Feldman AL, Johansson AL, Nise G, et al. (2011) Occupational exposure in Parkinsonian disorders: a 43-year prospective cohort study in men. Parkinsonism Relat D 17: 677-682. doi: 10.1016/j.parkreldis.2011.06.009
[166]	Kiesswetter E, Schäper M, Buchta M, et al. (2009) Longitudinal study on potential neurotoxic effects of aluminium: II. Assessment of exposure and neurobehavioral performance of Al welders in the automobile industry over 4 years. Int Arch Occ Env Hea 82: 1191-1210.
[167]	Fored CM, Fryzek JP, Brandt L, et al. (2006) Parkinson's disease and other basal ganglia or movement disorders in a large nationwide cohort of Swedish welders. Occup Environ Med 63: 135-140. doi: 10.1136/oem.2005.022921
[168]	Santamaria AB, Cushing CA, Antonini JM, et al. (2007) State-of-the-science review: does manganese exposure during welding pose a neurological risk? J Toxicol Env Heal B 10: 417-465. doi: 10.1080/15287390600975004
[169]	Racette BA, Criswell SR, Lundin JI, et al. (2012) Increased risk of parkinsonism associated with welding exposure. Neurotoxicology 33: 1356-1361. doi: 10.1016/j.neuro.2012.08.011
[170]	Bowler RM, Roels HA, Nakagawa S, et al. (2007) Dose-effect relationships between manganese exposure and neurological, neuropsychological and pulmonary function in confined space bridge welders. Occup Environ Med 64: 167-177. doi: 10.1136/oem.2006.028761
[171]	Racette BA, Tabbal SD, Jennings D, et al. (2005) Prevalence of parkinsonism and relationship to exposure in a large sample of Alabama welders. Neurology 64: 230-235. doi: 10.1212/01.WNL.0000149511.19487.44
[172]	National Research Council (2006) Health Risks from Exposure to Low Levels of Ionizing Radiation: BEIR VII Phase 2. Washington, DC: National Academies Press.
[173]	Shrader-Frechette KS (2008) Ideological toxicology: invalid logic, science, ethics about low-dose pollution. Hum Exp Toxicol 27: 647-657. doi: 10.1177/0960327108098491
[174]	Shrader-Frechette KS (2010) Conceptual analysis and special-interest science. Synthese 177: 449-469. doi: 10.1007/s11229-010-9792-5
[175]	Thayer KA, Melnick R, Burns K, et al. (2005) Fundamental Flaws of Hormesis for Public Health Decisions. Environ Health Persp 113: 1272-1275.
[176]	Urani C., Melchioretto P, Fabbri M., et al. (2014). Cadmium impairs p53 activity in hepG2 cells. ISRN Toxicol. Article ID 0976428http: //dx.doi.org/10.1155/2014/976428
[177]	Bal W, Protas AM, Kasprzak KS (2011) Genotoxicity of metal ions. Met Ions Life Sci 8: 319-373.
[178]	Shrader-Frechette K (2011). What Will Work: Fighting Climate Change with Renewable Energy, Not Nuclear Power. New York: Oxford University Press.

Reader Comments

Your name:*

Email:*
© 2015 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)