Parkinson disease (PD) is a progressive neurodegenerative movement disorder that affects 1% of people over the age of 55, increasing to 5% by 85 years of age. Although the average age of onset is 70 years old, a significant number of patients (~4%) will develop early-onset PD, which can occur before they are 50 years old (Farrer, 2006
). Clinically, PD is predominantly defined as a movement disorder, characterized by an alteration in the ability to initiate and maintain normal movement, manifesting as slowness of movement, a resting tremor, and postural instability. These symptoms are a direct result of the loss of dopamine-producing neurons located in the substantia nigra pars compacta (SNpc) of the midbrain and a concomitant reduction of the neurotransmitter dopamine and dopaminergic terminals in the caudate and putamen of the striatum (Fahn, 2003
). These deficits can be readily assessed in the awake patient through the use of several imaging techniques, including positron emission tomography (PET) and single photon emission computer tomography (SPECT), which both incorporate the use of ligands that are specific for dopaminergic transporters or receptors. Importantly, many of these motor symptoms can be alleviated, albeit not completely or permanently, through dopamine replacement therapies, such as L-DOPA (Fahn et al., 2004
In addition to motor abnormalities, PD patients can also present with a suite of non-motor problems that accompany or may even precede the motor issues and can range from gastrointestinal and cognitive deficits to olfactory and sleep disturbances. While damage to the nigrostriatal dopamine system underlies the motor perturbations, many of the peripheral alterations are thought to arise from damage to other neurotransmitter systems, including loss of noradrenergic neurons and projections from the locus coeruleus as well as cholinergic deficits in the nucleus basalis of Meynert (Fahn, 2003
It should be kept in mind that PD is only a singular syndrome that is a part of a much larger clinico-pathological definition of movement disorders, defined as parkinsonism (Tuite and Krawczewski, 2007
). Parkinsonism encompasses multiple different movement disorders that all seem to share a similar tetrad of movement deficits, including rigidity, tremor, slowness of movement, and postural instability, although these may be present in different combinations. The etiology of these deficits is extremely varied, ranging from multiple systems atrophy and progressive supranuclear palsy to drug- or toxicant-induced syndromes, such as carbon monoxide and manganese. Furthermore, the cause of parkinsonism will be further defined by the presence or absence of pathological signs and symptoms. For instance, while PD shows a discrete loss of dopaminergic neurons in the SNpc and a favorable response to dopamine replacement therapy, other conditions such as parkinsonism as a result of manganese toxicity do not (Guilarte, 2010
). It can be appreciated that this spectrum of parkinsonian clinico-pathological presentations can significantly complicate the differential diagnosis of PD and other parkinsonian disorders.
Although PD is primarily viewed as a disease of aging the signs and symptoms of PD can be accelerated through a genetic predisposition to the disease or exposure to an environmental risk factor (Farrer, 2006
). To date, mutations to several genes have been identified as genetic risk factors for the disease, yet these genetic alterations are only able to account for 5–10% of the cases of PD. This would suggest that there are exogenous or environmental factors that influence the risk of development of PD, that either work independently or in conjunction with genetic predisposition to facilitate the onset of the disease (Gao and Hong, 2011
Indeed, work over the last several decades has provided extensive support for the idea that exposure to different environmental factors could be a significant risk factor for the development of PD (Wirdefeldt et al., 2011
). The first indication that an exogenous insult could be responsible came in the form of I.V. drug users who had injected a synthetic meperidine compound that was contaminated with the neurotoxic species, 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causing an acute onset of an irreversible parkinsonian state that resembled idiopathic PD (Langston et al., 1983
, Markey et al., 1984
). MPTP is rapidly taken up into the brain and quickly converted to its neurotoxic metabolite, MPP+ by astrocytes. It is then extruded from the astrocytes by the organic cation transporter 3 (Cui et al., 2009
). Once in the extracellular space MPP+ is shuttled through the dopamine transporter located on the presynaptic terminal of dopamine neurons and is transported into the mitochondria where it inhibits mitochondrial respiration, resulting in the death of dopaminergic neurons and their projections in the SNpc and striatum, respectively. The role of an environmental factor or factors was further bolstered through a series of epidemiological studies that examined the incidence of PD in mono- and dizygotic twins (Tanner et al., 1999
). Through this work it was uncovered that the incidence of PD in each of these groups was virtually identical suggesting the heritability of PD was low. More importantly, it provided evidence that an exogenous factor was significantly influencing the relative risk of PD.
While multiple studies have provided extensive support for an environmental role in the etiopathogenesis of PD, the identification of certain settings or toxicants has remained relatively elusive. However, in the last several years a significant effort has been made to identify particular toxicants or classes of toxicants, which may promote the development of the disorder. While exposure to pesticides and other agricultural products has received a considerable amount of attention and has been demonstrated to be a substantial contributor to the incidence of PD, they represent only a single class of environmental toxicants to which the human population is routinely exposed (Priyadarshi et al., 2000
, Ascherio et al., 2006
). The reader is referred to other reviews on the subject (Dick et al., 2007
, Hatcher et al., 2008
). In addition to agricultural products, industrial contaminants are beginning to receive recognition as potential risk factors for the development of PD (Steenland et al., 2006
, Goldman, 2010
, Seegal et al., 2010
). Industrial toxicants are a broad and diverse class of compounds that are utilized in the manufacture and production of various commercial and household products, ranging from the use of carbon disulfide in the vulcanization of rubber to brominated flame retardants in the insulation of electrical components in a computer. As with pesticides, the human population is routinely exposed to industrial toxicants, either through an occupational setting or via contaminated food or their presence in everyday household products.
In this review we will direct our focus to relevant clinical and research findings, that provide support for the role of industrial toxicants in the etiology of PD and other parkinsonian disorders. Our decisions for and discussion of a particular compound was based upon its adherence to one or more criteria: 1). Has this compound been associated with PD in the human population? 2). Does exposure to this compound produce a movement disorder associated with PD or parkinsonism in the human population? 3). Does the compound target similar mechanisms and produce a similar pathology as that seen in PD?
Organohalogen Industrial Contaminants
Organohalogenated compounds (OHC) are a class of carbon-containing chemicals with varying degrees of halogen substitution on carbon atoms. The most prevalent halogen substitutions are comprised of chlorine, bromine, and fluorine to produce organochlorine, organobromine, and organofluorine compounds, respectively. The use of these compounds in an industrial setting is varied and can range from electrical insulating coatings, flame-retardant oils and in adhesives and plastics. The same properties that have made these compounds so attractive to industrial use, including being highly stable and resistant to degradation, have also made them extremely dangerous to the environment and the human population. Although there are several different compounds that are classified as being organohalogens, we will focus our discussion on the two that have received the most attention given their effects on the brain and as a risk factor for PD.