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Parkinson's Disease and Residential Exposure to Maneb and Paraquat From Agricultural Applications in the Central Valley of California


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Evidence from animal and cell models suggests that pesticides cause a neurodegenerative process leading to Parkinson's disease (PD). Human data are insufficient to support this claim for any specific pesticide, largely because of challenges in exposure assessment. The authors developed and validated an exposure assessment tool based on geographic information systems that integrated information from California Pesticide Use Reports and land-use maps to estimate historical exposure to agricultural pesticides in the residential environment. In 1998–2007, the authors enrolled 368 incident PD cases and 341 population controls from the Central Valley of California in a case-control study. They generated estimates for maneb and paraquat exposures incurred between 1974 and 1999. Exposure to both pesticides within 500 m of the home increased PD risk by 75% (95% confidence interval (CI): 1.13, 2.73). Persons aged ≤60 years at the time of diagnosis were at much higher risk when exposed to either maneb or paraquat alone (odds ratio = 2.27, 95% CI: 0.91, 5.70) or to both pesticides in combination (odds ratio = 4.17, 95% CI: 1.15, 15.16) in 1974–1989. This study provides evidence that exposure to a combination of maneb and paraquat increases PD risk, particularly in younger subjects and/or when exposure occurs at younger ages.
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American Journal of Epidemiology
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Vol. 169, No. 8
DOI: 10.1093/aje/kwp006
Advance Access publication March 6, 2009
Original Contribution
Parkinson’s Disease and Residential Exposure to Maneb and Paraquat From
Agricultural Applications in the Central Valley of California
Sadie Costello, Myles Cockburn, Jeff Bronstein, Xinbo Zhang, and Beate Ritz
Initially submitted September 12, 2008; accepted for publication January 6, 2009.
Evidence from animal and cell models suggests that pesticides cause a neurodegenerative process leading to
Parkinson’s disease (PD). Human data are insufficient to support this claim for any specific pesticide, largely
because of challenges in exposure assessment. The authors developed and validated an exposure assessment
tool based on geographic information systems that integrated information from California Pesticide Use Reports
and land-use maps to estimate historical exposure to agricultural pesticides in the residential environment. In
1998–2007, the authors enrolled 368 incident PD cases and 341 population controls from the Central Valley of
California in a case-control study. They generated estimates for maneb and paraquat exposures incurred between
1974 and 1999. Exposure to both pesticides within 500 m of the home increased PD risk by 75% (95% confidence
interval (CI): 1.13, 2.73). Persons aged 60 years at the time of diagnosis were at much higher risk when exposed
to either maneb or paraquat alone (odds ratio ¼2.27, 95% CI: 0.91, 5.70) or to both pesticides in combination
(odds ratio ¼4.17, 95% CI: 1.15, 15.16) in 1974–1989. This study provides evidence that exposure to a combi-
nation of maneb and paraquat increases PD risk, particularly in younger subjects and/or when exposure occurs at
younger ages.
case-control studies; fungicides, industrial; geographic information systems; herbicides; maneb; paraquat;
Parkinson disease; pesticides
Abbreviations: CI, confidence interval; DDE, dichlorodiphenyldichloroethylene; GIS, geographic information system; MPPþ, toxic
metabolite of 1-methyl-4-phenylpyridinium; OR, odds ratio; PD, Parkinson’s disease; PLSS, Public Land Survey System; PUR,
Pesticide Use Reporting.
Parkinson’s disease (PD) has been reported to occur at
high rates among farmers and in rural populations, contrib-
uting to the hypothesis that agricultural pesticides might be
causal agents (1–4). Animal studies have linked certain pes-
ticides to Parkinsonism and dopaminergic cell death. The
pesticide rotenone can produce the behavioral and neuro-
pathologic features of PD in some rodent models through
chronic systemic inhibition of mitochondrial complex I (5,
6). Exposure to a combination of the fungicide maneb and
the herbicide paraquat in mice leads to increased substantia
nigra neuronal pathology (7), age-dependent motor degen-
eration, progressive reductions in dopamine metabolites and
turnover (8), and reduced tyrosine hydroxylase and dopa-
mine transporter immunoreactivity (9, 10).
Human evidence is insufficient to identify any particular
pesticide compound, including those implicated by animal
studies, as being responsible for causing PD (11). Method-
ological limitations have clouded the interpretation of most
epidemiologic studies exploring pesticide exposures and PD
in humans. Past studies have generally relied on self-reports
and recall of chemical usage, making them vulnerable to
information bias and differential recall bias (12).
Because pesticides applied from the air or ground may
drift from their intended treatment sites, with measurable
concentrations subsequently detected in the air, in plants,
and in animals up to several hundred meters from applica-
tion sites (13–15), accurate methods of estimating environ-
mental exposures in rural communities are sorely needed.
Correspondence to Dr. Sadie Costello, Department of Environmental Health Sciences, School of Public Health, University of California, Berkeley,
50 University Hall, #7360, Berkeley, CA 94720-7360 (e-mail:
919 Am J Epidemiol 2009;169:919–926
Geographic information system (GIS)-based methods of as-
sessing exposure to pesticides have become popular in re-
cent years and may prove an effective solution when
pesticide data exist. We developed and employed a validated
GIS-based exposure assessment tool to estimate pesticide
exposure from applications to agricultural crops, relying
on California Pesticide Use Reporting (PUR) data, land-
use maps, and geocoded residential historical locations
(16). We investigated whether exposure to the pesticides
maneb and paraquat, alone and in combination, increased
the risk of incident PD among residents of the Central Valley
of California, an area well-known for its intensive agricul-
ture and potential for pesticide exposure.
All procedures described have been approved by the
University of California, Los Angeles, institutional review
board for human subjects, and informed consent was ob-
tained from all participants.
Subject recruitment
We used a population-based approach for recruiting cases
and controls from a largely agricultural population in Cali-
fornia. Details are provided elsewhere (17). Briefly, persons
with PD newly diagnosed between January 1998 and January
2007 who resided in 1 of 3 central California counties
(Fresno, Tulare, or Kern county) and had lived in California
for at least 5 years prior to diagnosis were recruited into our
study within 3 years of diagnosis. Altogether, 28 (90%) of
the 31 practicing local neurologists who provided care for
PD patients assisted in recruiting cases for this study. We
solicited collaboration from Kaiser Permanente Medical
Center (Fresno, California), Kern Medical Center (Bakersfield,
California), and Visalia Medical Clinic (Visalia, California)
and from the Veterans Administration, PD support groups,
local newspapers, and local radio stations that broadcast
public service announcements.
Of the 1,167 PD cases who were initially invited, 604
were not eligible: For 397, the case’s diagnosis date fell
outside the 3-year range prior to contact, 51 denied having
received a PD diagnosis, 134 lived outside the tricounty
area, and 22 were too ill to participate. Of the 563 eligible
cases, 473 (84%) were examined by a University of Cali-
fornia, Los Angeles, movement disorder specialist at least
once and were confirmed to have clinically ‘‘probable’’ or
‘‘possible’’ PD; the remaining 90 potential cases could not
be examined or interviewed (54% withdrew, 32% were too
ill or died, and 14% moved out of the area prior to the
examination or did not honor a scheduled appointment).
We examined but excluded another 96 patients because they
had other causes of Parkinsonism. This left us with 377
cases; of these, 368 provided all information needed for
Controls aged 65 years or older were identified from
Medicare lists in 2001, but because of implementation of
the Health Insurance Portability and Accountability Act,
which prohibits the use of Medicare enrollees, 70% of our
controls were recruited from randomly selected tax assessor
residential units (parcels) in each of the 3 counties. We
mailed letters of invitation to a random selection of residen-
tial living units and also attempted to identify head-of-
household names and telephone numbers for these parcels,
using the services of marketing companies and Internet
We contacted 1,212 potential population controls by mail
and/or telephone for eligibility screening. Eligibility criteria
were: 1) not having PD, 2) being at least 35 years of age,
3) currently residing primarily in 1 of the 3 designated coun-
ties, and 4) having lived in California for at least 5 years
prior to the screening. Only 1 person per household was
allowed to enroll. Of the potential controls contacted, 457
were ineligible: 409 were too young, 44 were terminally ill,
and 4 resided primarily outside of the study area. Of the 755
eligible controls, 409 (54%) declined participation, were too
ill to honor an appointment, or moved out of the area prior to
interview; 346 (46%) were enrolled, and 341 provided all
information needed for analyses.
Assessment of environmental pesticide exposure
We conducted telephone interviews to obtain demo-
graphic and exposure information. Detailed residential his-
tory forms were mailed to subjects in advance of their
interview and were reviewed in person or over the phone.
We estimated pesticide exposures in the residential environ-
ment from applications to agricultural crops employing
a validated GIS-based system, which combined PUR data
and land-use maps (16, 18), to produce estimates of residen-
tial ambient pesticide applications within a set distance of
subjects’ homes. We recorded and geocoded lifetime resi-
dential histories and estimated ambient exposures for all
historical addresses at which participants had resided be-
tween 1974 and 1999, the period covered by the PUR data.
A technical discussion of our GIS-based approach is pro-
vided elsewhere (16); here we briefly summarize the data
sources and the exposure modeling process.
Residential addresses. Addresses were automatically
geocoded to TigerLine files (NAVTEQ (Chicago, Illinois),
unpublished data, 2006), and discrepancies were then man-
ually resolved in a multistep process similar to that de-
scribed by McElroy et al. (19). Resulting locations were
recorded, along with the relevant year range of residence,
so they could be matched to the appropriate year-specific
PUR and land-use data (below). For our GIS model, we
relied on addresses in Fresno, Kern, and Tulare counties
(the tricounty area) at which participants had resided be-
tween 1974 and 1999. Out of 9,568 total residential years
contributed by cases (26 years 3368 cases), 7,593 years
(79%) were spent at addresses within the tricounty area as
compared with 6,757 (76%) of 8,866 years contributed by
controls (26 years 3341 controls). We geocoded these
tricounty residential addresses for the period 1974–1999
with similar precision for cases and controls; that is, both
had spent 88% of their respective residential years at ad-
dresses we considered to have been mapped with high pre-
cision (i.e., at the level of a residential parcel, street
address, or street intersection rather than a zip code or city
920 Costello et al.
Am J Epidemiol 2009;169:919–926
Pesticide use reporting. PUR data are recorded by the
California Department of Pesticide Regulation for any com-
mercial application of restricted-use pesticides (defined as
agents with harmful environmental or toxicologic effects
(20)) and, since 1990, for all commercial uses of pesticides
regardless of toxicologic profile. The location of each PUR
record is referenced to the Public Land Survey System
(PLSS), a nationwide grid that parcels land into sections
at varying resolutions. Each PUR record includes the name
of the pesticide’s active ingredient, the poundage applied,
the crop and acreage of the field, the application method,
and the date of application.
Land-use maps. Because the PUR records link an agri-
cultural pesticide application only to a whole PLSS grid
section, we added information from land-use maps to more
precisely locate the pesticide application, as described in
detail elsewhere (18). The California Department of Water
Resources periodically (every 7–10 years) performs county-
wide large-scale surveys of land use and crop cover, which
allowed us to identify the locations of specific crops within
each PLSS grid section. Digital maps from more recent
(1996–1999) surveys are available (21), and paper maps
were manually digitized for earlier periods (1977–1995).
The 1977 land-use survey was conducted closest in time
to 1974, when PUR data became available. We constructed
historical electronic maps of land use and crop type, and
using the PLSS grid section and the crop type reported in the
PUR record, we allocated pesticide applications to an agri-
cultural site to which we assigned a GIS-based location.
Deriving estimates of residential pesticide exposure. The
time-specific total exposure at each location, by pesticide,
was derived through summation of exposures over a fixed
500-m radius (suggested in previous literature (13, 15, 19))
around the home for the relevant years of residence. The
numbers of pounds of pesticide applied annually per acre
were summed for each residential buffer and weighted by
the proportion of treated acreage in each buffer, resulting in
pesticide application rates that could be averaged over spe-
cific calendar periods of each subject’s lifetime.
Statistical analysis
We estimated residential exposures to maneb and para-
quat, alone and in combination, for the following time win-
dows: 1) 1974–1999, 2) 1974–1989, and 3) 1990–1999, to
assess the possibility of an extensive induction period prior
to PD onset and the influence of age at exposure. We strat-
ified models by sex and age (60 years, >60 years) and, in
additional sensitivity analyses, controlled for exposure to
some groups of pesticides suspected to increase PD risk.
We controlled for occupational exposure to pesticides
among subjects who had held jobs in the agricultural sector,
assigning them to categories of ‘‘likely exposed to pesti-
cides’’ when they reported pesticide handling and applica-
tions or fieldwork and ‘‘possibly exposed to pesticides’
when they reported managerial, produce processing, and
other nonfield farm work; all other subjects were considered
‘‘not occupationally exposed to pesticides’’ (22). In some
models, we also adjusted for residential exposures to groups
of other pesticides that some studies have found to be linked
to dopaminergic cell damage or possibly PD (organochlo-
rines, organophosphates, and dithiocarbamates (23) and pro-
teasome inhibitors (24)).
We considered the following demographic variables as
potential confounders in all analyses: age (age at diagnosis
for cases and age at interview for controls), sex, race (white,
nonwhite), education (<12 years, 12 years, >12 years), and
cigarette smoking (current, former, never). We used SAS 9.1
(SAS Institute Inc., Cary, North Carolina) to perform un-
conditional logistic regression analyses.
Study participants were predominantly Caucasian, over
the age of 60, and without a family history of PD (Table 1).
Cases were slightly older than controls, were more often
male, and had completed fewer years of education. They
were also more likely to have been occupationally exposed
to pesticides and to be never or former smokers.
We did not find increased risks of PD among subjects
exposed to paraquat alone during the years 1974–1999
(Table 2). While the rarity of sole maneb exposure (4 subjects)
precluded any meaningful interpretation of the maneb-only
results, combined exposure to both maneb and paraquat in-
creased the risk of PD by 75% (odds ratio (OR) ¼1.75,
95% confidence interval (CI): 1.13, 2.73), an effect estimate
which was essentially unchanged after adjustment for
occupational pesticide exposure (OR ¼1.74, 95% CI:
1.11, 2.72).
When we examined 2 separate exposure time windows,
the years 1974–1989 and 1990–1999, the risk increase ob-
served for the whole period was found to be mainly attribut-
able to exposures incurred during the earlier window
(OR ¼2.14, 95% CI: 1.24, 3.68), while being exposed
during the later window did not seem to increase PD risk
(Table 2). Furthermore, for younger (60 years) subjects,
exposure to both maneb and paraquat in both windows in-
creased PD risk as much as 4- to 6-fold (Table 3). Exposure
to either maneb or paraquat alone during 1974–1989 also
increased risk of PD in younger subjects (OR ¼2.27, 95%
CI: 0.91, 5.70). When we examined exposure windows
among our older subjects (>60 years), combined exposure
to both pesticides in the earlier window only (1974–1989)
was also associated with a 2-fold increase in PD risk
(OR ¼2.15, 95% CI: 1.15, 4.02), but no increase was found
for either the later window (1990–1999) or the combined
exposure periods (Table 3). Stratification by sex suggested
no differences in estimates between males and females.
In this population-based case-control study, agricultural
application of both maneb and paraquat within 500 m of
a residence during the period 1974–1999 greatly increased
the risk of developing PD, especially when exposure oc-
curred between 1974 and 1989 or when PD was diagnosed
at a younger age (60 years). Exposure to both pesticides
during the earlier time window (1974–1989) also doubled
the risk for older cases. Associations were particularly
PD and Residential Maneb and Paraquat Exposure 921
Am J Epidemiol 2009;169:919–926
strong for younger-onset patients (60 years), who would
have been children, teenagers, and young adults during the
exposure period: Among those exposed in the earlier time
window, risk was increased more than 4-fold with exposure
to both pesticides and more than 2-fold with exposure to just
1 of the pesticides. Consistent with some theories regarding
the progression of PD pathology (25), these data suggest
that the critical window of exposure to toxicants may be
years before the onset of motor symptoms which lead to
Pesticide and herbicide exposures have previously been
implicated in idiopathic PD. Paraquat is structurally similar
to the toxic metabolite (MPPþ) of the 1-methyl-4-phenyl-
pyridinium ion (a metabolite of 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine), an agent known to induce Parkinsonian
symptoms in humans that has been widely used to study
Table 1. Odds Ratio for Parkinson’s Disease According to Various Sociodemographic
Characteristics, Central Valley of California, 1998–2008
(n5341) Odds
No. or Mean % No. or Mean %
Mean age,
years (range)
68.1 (34–88) 67.6 (34–92) 1.00 0.99, 1.02
Age group, years
40 7262
41–50 25 7 26 8
51–60 47 13 55 16
61–70 111 30 95 28
71–80 145 39 121 35
>80 33 9 38 11
Female sex 161 44 165 48 0.83 0.62, 1.12
First-degree relative with
Parkinson’s disease
55 15 37 11 1.44 0.93, 2.25
White 296 80 279 82 1 Reference
72 20 62 18 1.09 0.75, 1.60
Asian 4 1 8 2
Black 3 1 13 4
Latino 49 13 31 9
Native American 16 4 10 3
Education, years
<12 68 18 38 11 1.15 0.69, 1.90
12 100 27 64 19 1 Reference
>12 200 54 239 70 0.54 0.37, 0.77
Job exposure matrix
Not occupationally
exposed to pesticides
232 63 240 70 1 Reference
Possibly occupationally
exposed to pesticides
26 7 26 8 1.03 0.58, 1.83
Likely occupationally
exposed to pesticides
110 30 75 22 1.52 1.08, 2.14
Cigarette smoking status
Never smoker 195 53 146 43 1 Reference
Former smoker 151 41 161 47 0.70 0.52, 0.96
Current smoker 22 6 34 10 0.48 0.27, 0.86
Pack-years of
cigarette smoking
0 195 53 146 43 1 Reference
>0–19 96 26 89 26 0.81 0.56, 1.16
>19 77 21 106 31 0.54 0.38, 0.78
The odds ratio was calculated for all nonwhites versus whites.
922 Costello et al.
Am J Epidemiol 2009;169:919–926
Parkinsonism in animal models (26). MPPþis believed to
cause cell death by interfering with mitochondrial respira-
tion (27), because it concentrates in mitochondria and in-
hibits complex I of the electron transport chain (28). Many
lines of evidence point to possible mitochondrial dysfunc-
tion in PD. Several genes have been identified in familial
forms of PD that are linked to mitochondrial function
(PINK1 and DJ1), and in sporadic cases of PD, pathologic
free radical reactions that damage mitochondria and de-
crease electron transport activity have been described (29).
Impaired electron transport hampers adenosine triphosphate
production and leads to the diversion of electrons from their
normal electron transport recipients and, thus, further for-
mation of damaging free radicals (29).
Although paraquat is also used to induce Parkinsonism in
some animal models, the mechanism by which it produces
symptoms is not yet understood (30). Recent mammalian
and yeast-cell experiments suggest that mitochondria take
up paraquat actively across their membranes, where com-
plex I reduces it to the paraquat radical cation that subse-
quently produces mitochondria-damaging superoxide (31).
It has also been suggested that maneb may inhibit the ubiq-
uitin proteasome system, thereby damaging the dopaminer-
gic neuron (24, 32). Additionally, maneb has been linked to
Parkinsonism in mice also exposed to paraquat. In 3 recent
studies, investigators reported that only when mice were
exposed to a combination of the fungicide maneb and the
Table 2. Odds Ratio for Parkinson’s Disease According to
Residential Ambient Exposure to Maneb and/or Paraquat, Central
Valley of California, 1974–1999
Time Window
and Exposure
(n5341) Odds
No. % No. %
Missing data 13 4 13 4
No exposure 115 31 126 37 1 Reference
Paraquat only 149 40 152 45 1.01 0.71, 1.43
Maneb only 3 1 1 0 3.04 0.30, 30.86
Both paraquat
and maneb
88 24 49 14 1.75 1.13, 2.73
Missing data 53 14 52 15
No exposure 93 25 113 33 1 Reference
Paraquat or
maneb only
148 40 137 40 1.25 0.85, 1.85
Both paraquat
and maneb
74 20 39 11 2.14 1.24, 3.68
Missing data 15 4 15 4
No exposure 215 58 213 62 1 Reference
Paraquat or
maneb only
113 31 95 28 0.96 0.64, 1.43
Both paraquat
and maneb
25 7 18 5 0.93 0.45, 1.94
Odds ratios were adjusted for age, sex, nonwhite race, education,
and smoking status. Results were mutually adjusted for exposure in
each time window.
Table 3. Odds Ratio for Parkinson’s Disease According to
Residential Ambient Exposure to Maneb and/or Paraquat, by Time
Window of Exposure and Age Group, Central Valley of California,
Age Group
and Exposure
Cases Controls Odds
No. % No. %
1974–1999 Time Window
60 years
Missing data 2 3 4 5
No exposure 18 23 34 39 1 Reference
Paraquat or
maneb only
38 48 42 48 1.77 0.84, 3.75
Both paraquat
and maneb
21 27 7 8 5.07 1.75, 14.71
>60 years
Missing data 11 4 9 4
No exposure 97 34 92 36 1 Reference
Paraquat or
maneb only
114 39 111 44 0.90 0.60, 1.34
Both paraquat
and maneb
67 23 42 17 1.36 0.83, 2.23
1974–1989 Time Window
60 years
Missing data 16 20 20 23
No exposure 13 16 27 31 1 Reference
Paraquat or
maneb only
36 46 34 39 2.27 0.91, 5.70
Both paraquat
and maneb
14 18 6 7 4.17 1.15, 15.16
>60 years
Missing data 37 13 32 13
No exposure 80 28 86 34 1 Reference
Paraquat or
maneb only
112 39 103 41 1.18 0.75, 1.84
Both paraquat
and maneb
60 21 33 13 2.15 1.15, 4.02
1990–1999 Time Window
60 years
Missing data 2 3 5 6
No exposure 43 54 58 67 1 Reference
Paraquat or
maneb only
27 34 22 25 2.00 0.84, 4.74
Both paraquat
and maneb
7 9 2 2 5.74 0.55, 59.62
>60 years
Missing data 13 4 10 4
No exposure 172 60 155 61 1 Reference
Paraquat or
maneb only
86 30 73 29 0.78 0.49, 1.24
Both paraquat
and maneb
18 6 16 6 0.66 0.29, 1.50
Age-stratified models with adjustment for sex, nonwhite race,
education, and smoking status. Results were mutually adjusted for
exposure in each time window.
PD and Residential Maneb and Paraquat Exposure 923
Am J Epidemiol 2009;169:919–926
herbicide paraquat (paraquat þmaneb), not to either pesti-
cide alone, did they exhibit increased neuronal pathology
(7), age-dependent motor degeneration and progressive re-
ductions in dopamine metabolites and dopamine turnover
(8), and reduced tyrosine hydroxylase and dopamine trans-
porter immunoreactivity (9).
The fungicide maneb and the herbicide paraquat are both
used in the Central Valley of California and are often used
on the same crops, including potatoes, dry beans, and toma-
toes. The average amount of maneb applied near the homes
of these study subjects was relatively stable throughout both
time windows; however, annual paraquat exposure in-
creased during the later (1990–1999) time window. Persons
living near fields sprayed with maneb and paraquat may also
be exposed to a host of other agricultural chemicals. When
we controlled for the influence of other groups of pesticides
suspected a priori to be risk factors for PD in our study, the
odds ratios for combined maneb and paraquat exposure and
PD in the younger subjects were still in the 3- to 6-fold range
and statistically significant; however, our precision de-
creased, probably because of correlated exposures. Correla-
tion between pesticides is an inherent problem when
assessing the effects of human exposure. However, since
adjustment for other pesticides did not remove the associa-
tion for maneb and paraquat, our data provide compelling
evidence that these 2 pesticides may in fact affect PD risk in
humans, as has been suggested by animal experiments.
Paraquat and maneb are applied by ground, aerial, and
backpack methods; however, paraquat has a much longer
field half-life of 1,000 days (33), as compared with only
12–36 days for maneb (34). Both chemicals bind strongly
to soil, though, and are not thought to be a threat to ground-
water (35, 36). Such strong binding could result in contam-
inated soil getting blown or tracked into homes by wind,
pets, and shoes, thereby increasing exposure for persons
who live closer to agricultural application sites (3, 37, 38).
In a previous validation study, our prediction model for a
serum measure of dichlorodiphenyldichloroethylene (DDE)
explained 47% of the biomarker’s variance (39). Addition-
ally, our GIS-derived measure of organochlorine exposure
identified persons with high serum DDE levels reasonably
well (specificity of 87%) (39).
Although our GIS model allowed us to calculate the num-
ber of pounds of each active ingredient applied per acre
within a 500-m buffer, these quantities are not comparable
across pesticides. That is, a pound of active ingredient does
not represent the same human neurotoxicity across pesti-
cides, and no information currently exists that would allow
us to standardize these measures. Thus, while we believe
that our model provided us with an accurate indicator of any
pesticide exposure from applications close to a residence,
our exposure measure cannot be considered quantitative
beyond a crude rank ordering of low/medium likelihood
of exposure and high likelihood of exposure. Since we hy-
pothesized that coexposure to 2 pesticides, maneb and para-
quat, would increase the risk of PD, we also lacked the
statistical power to perform extensive categorical analyses
(note that only 3 cases and 1 control were exposed solely to
maneb). We conducted additional analyses after dichoto-
mizing pounds per acre at their median and mean levels
and found that exposure to both pesticides at the highest
level was associated with PD, especially in persons aged
60 years; however, wide confidence intervals surrounding
our point estimates rendered these results generally uninfor-
mative (results not shown).
In only 1 previous analysis, conducted within the Agri-
cultural Health Study cohort (40), did researchers assess the
effects of maneb and paraquat exposures. Statistical power
was limited by the small number (n¼78) of incident cases
identified during follow-up and the very small number (n¼
4–10) of cases exposed to maneb/mancozeb (OR ¼2.1) and
paraquat (OR ¼1.4). In a small Taiwanese study, the only
case-control study to date with sufficient statistical power to
examine exposure to the herbicide paraquat, Liou et al. (41)
reported a 4- to 6-fold increase in PD risk among long-term
applicators. In a case-control study from the Mayo Clinic
(Rochester, Minnesota), Brighina et al. (42) presented asso-
ciations between self-reported pesticide exposure and PD in
subjects younger than 60 years only (for all pesticides,
OR ¼1.80, 95% CI: 1.12, 2.87; for herbicides, OR ¼2.46,
95% CI: 1.34, 4.52).
Our exposure estimates did not depend on the subject’s
recall of pesticide exposure and are therefore unlikely to
have been biased by differential exposure misclassification.
Since all of our PD diagnoses were clinically confirmed, we
expect disease misclassification to have been minimal. Non-
differential exposure misclassification is a possibility in our
study and may have attenuated our effect estimates.
Our results may be biased if cases and controls selected
themselves into our study according to their potential for
pesticide exposure, but our subjects were not asked to self-
report environmental exposures and probably were unaware
of their true historical exposures. There is no reason to
suspect that cases and controls would have chosen to par-
ticipate on the basis of their historical residence near certain
agricultural plots. We saw no difference in estimated effects
when we restricted analyses to only those subjects with
more (12 years) or less (<12 years) education. Similarly,
we saw no difference in our results when we restricted the
sample to persons whose addresses had been mapped with
high precision in the tricounty area during the period 1974–
1999 (363 cases, 336 controls).
Our analysis has confirmed 2 previous observations from
animal studies: 1) exposure to multiple chemicals may po-
tentiate the effect of each chemical (of interest, since hu-
mans are often exposed to more than 1 pesticide in the
environment) and 2) the timing of exposure is important.
To our knowledge, this is the first epidemiologic study to
provide strong evidence that 2 specific pesticides, suggested
by animal research as potentially acting synergistically to
become neurotoxic, strongly increase the risk of PD in
humans, especially given combined exposure and when
encountered earlier in life.
Author affiliations: Department of Environmental Health
Sciences, School of Public Health, University of California,
924 Costello et al.
Am J Epidemiol 2009;169:919–926
Berkeley, Berkeley, California (Sadie Costello); Department
of Preventive Medicine, Keck School of Medicine, Univer-
sity of Southern California, Los Angeles, California (Myles
Cockburn, Xinbo Zhang); Department of Geography, College
of Letters, Arts and Sciences, University of Southern
California, Los Angeles, California (Myles Cockburn,
Xinbo Zhang); Department of Neurology, School of Medicine,
University of California, Los Angeles, Los Angeles, Cali-
fornia (Jeff Bronstein); and Department of Epidemiology,
School of Public Health, University of California, Los
Angeles, Los Angeles, California (Beate Ritz).
This work was supported by the National Institute
of Environmental Health Sciences (grants ES10544,
U54ES12078, and 5P30 ES07048), the National Institute of
Neurological Disorders and Stroke (grant NS 038367), and
the Department of Defense Prostate Cancer Research Pro-
gram (grant 051037). In addition, initial pilot funding was
provided by the American Parkinson’s Disease Association.
The authors thank the participating neurologists and med-
ical centers in Fresno, Kern, and Tulare counties for their
Conflict of interest: none declared.
1. Ben-Shlomo Y, Finnan F, Allwright S, et al. The epidemiology
of Parkinson’s disease in the Republic of Ireland: observations
from routine data sources. Ir Med J. 1993;86(6):190–191, 194.
2. Burguera JA, Catala J, Taberner P, et al. Mortality from
Parkinson’s disease in Spain (1980–1985). Distribution by age,
sex and geographic areas. Neurologia. 1992;7(3):89–93.
3. Morano A, Jimenez-Jimenez FJ, Molina JA, et al. Risk-factors
for Parkinson’s disease: case-control study in the province of
´ceres, Spain. Acta Neurol Scand. 1994;89(3):164–170.
4. Svenson LW, Platt GH, Woodhead SE. Geographic variations
in the prevalence rates of Parkinson’s disease in Alberta. Can J
Neurol Sci. 1993;20(4):307–311.
5. Betarbet R, Sherer TB, MacKenzie G, et al. Chronic systemic
pesticide exposure reproduces features of Parkinson’s disease.
Nat Neurosci. 2000;3(12):1301–1306.
6. Sherer TB, Betarbet R, Greenamyre JT. Pesticides and
Parkinson’s disease. Scientific World Journal. 2001;1:207–208.
7. Norris EH, Uryu K, Leight S, et al. Pesticide exposure exac-
erbates alpha-synucleinopathy in an A53T transgenic mouse
model. Am J Pathol. 2007;170(2):658–666.
8. Thiruchelvam M, McCormack A, Richfield EK, et al. Age-
related irreversible progressive nigrostriatal dopaminergic
neurotoxicity in the paraquat and maneb model of the
Parkinson’s disease phenotype. Eur J Neurosci. 2003;18(3):
9. Thiruchelvam M, Richfield EK, Baggs RB, et al. The nigro-
striatal dopaminergic system as a preferential target of repeated
exposures to combined paraquat and maneb: implications for
Parkinson’s disease. J Neurosci. 2000;20(24):9207–9214.
10. Thiruchelvam M, Richfield EK, Goodman BM, et al. Devel-
opmental exposure to the pesticides paraquat and maneb and
the Parkinson’s disease phenotype. Neurotoxicology. 2002;
11. Brown TP, Rumsby PC, Capleton AC, et al. Pesticides and
Parkinson’s disease—is there a link? Environ Health Perspect.
12. Seidler A, Hellenbrand W, Robra BP, et al. Possible environ-
mental, occupational, and other etiologic factors for
Parkinson’s disease: a case-control study in Germany.
Neurology. 1996;46(5):1275–1284.
13. Chester G, Ward RJ. Occupational exposure and drift hazard
during aerial application of paraquat to cotton. Arch Environ
Contam Toxicol. 1984;13(5):551–563.
14. Currier WW, MacCollom GB, Baumann GL. Drift residues
of air-applied carbaryl in an orchard environment. J Econ
Entomol. 1982;75(6):1062–1068.
15. MacCollom GB, Currier WW, Baumann GL. Drift compari-
sons between aerial and ground orchard application. J Econ
Entomol. 1986;79(2):459–464.
16. Goldberg DW, Wilson JP, Knoblock CA, et al. An effective
and efficient approach for manually improving geocoded data.
Int J Health Geogr. 2008;7:60.
17. Kang GA, Bronstein JM, Masterman DL, et al. Clinical
characteristics in early Parkinson’s disease in a central
California population-based study. Mov Disord. 2005;20(9):
18. Rull RP, Ritz B. Historical pesticide exposure in California
using pesticide use reports and land-use surveys: an assess-
ment of misclassification error and bias. Environ Health
Perspect. 2003;111(12):1582–1589.
19. McElroy JA, Remington PL, Trentham-Dietz A, et al. Geo-
coding addresses from a large population-based study: lessons
learned. Epidemiology. 2003;14(4):399–407.
20. United States Senate Committee on Agriculture, Nutrition
and Forestry. Federal Insecticide, Fungicide, and
Rotenticide Act [As Amended Through P.L. 110–246,
Effective May 22, 2008]. Section 3(d)(1)(C).
Washington, DC: US Senate, 2008:30. (http://agriculture.
(Accessed February 8, 2009).
21. California Department of Water Resources. California Land
and Water Use. Sacramento, CA: California Department of
Water Resources; 2009. (
gov/). (Accessed February 8, 2009).
22. Young HA, Mills PK, Riordan D, et al. Use of a crop and job
specific exposure matrix for estimating cumulative exposure to
triazine herbicides among females in a case-control study in
the Central Valley of California. Occup Environ Med. 2004;
23. Elbaz A, Tranchant C. Epidemiologic studies of environmental
exposures in Parkinson’s disease. J Neurol Sci. 2007;262(1-2):
24. Wang XF, Li S, Chou AP, et al. Inhibitory effects of pesticides
on proteasome activity: implication in Parkinson’s disease.
Neurobiol Dis. 2006;23(1):198–205.
25. Braak H, Del Tredici K, Ru
¨b U, et al. Staging of brain pa-
thology related to sporadic Parkinson’s disease. Neurobiol
Aging. 2003;24(2):197–211.
26. Langston JW, Ballard P, Tetrud JW, et al. Chronic Parkinson-
ism in humans due to a product of meperidine-analog syn-
thesis. Science. 1983;219(4587):979–980.
27. Sayre LM, Wang F, Hoppel CL. Tetraphenylborate potentiates
the respiratory inhibition by the dopaminergic neurotoxin
MPPþin both electron transport particles and intact mito-
chondria. Biochem Biophys Res Commun. 1989;161(2):
28. Singer TP, Ramsay RR. Mechanism of the neurotoxicity of
MPTP. An update. FEBS Lett. 1990;274(1-2):1–8.
29. Cassarino DS, Bennett JP Jr. An evaluation of the role of
mitochondria in neurodegenerative diseases: mitochondrial
mutations and oxidative pathology, protective nuclear
PD and Residential Maneb and Paraquat Exposure 925
Am J Epidemiol 2009;169:919–926
responses, and cell death in neurodegeneration. Brain Res
Brain Res Rev. 1999;29(1):1–25.
30. Dinis-Oliveira RJ, Remia
˜o F, Carmo H, et al. Paraquat
exposure as an etiological factor of Parkinson’s disease.
Neurotoxicology. 2006;27(6):1110–1122.
31. Cocheme HM, Murphy MP. Complex I is the major site of
mitochondrial superoxide production by paraquat. J Biol
Chem. 2008;283(4):1786–1798.
32. Zhou Y, Shie FS, Piccardo P, et al. Proteasomal inhibition
induced by manganese ethylene-bis-dithiocarbamate: rele-
vance to Parkinson’s disease. Neuroscience. 2004;128(2):
33. Extension Toxicology Network. EXTOXNET: Extension Tox-
icology Network. Pesticide Information Profiles. Paraquat.
Corvallis, OR: Oregon State University; 1996. (http://extoxnet. (Accessed June 5, 2008).
34. Extension Toxicology Network. EXTOXNET: Extension
Toxicology Network. Pesticide Information Profiles. Maneb.
Corvallis, OR: Oregon State University; 1996. (http://extoxnet. (Accessed June 5, 2008).
35. Environmental Protection Agency. R.E.D. [Reregistration
Eligibility Decision] Facts. Paraquat Dichloride. Washington,
DC: Environmental Protection Agency; 1997. (http://www. (Accessed
June 5, 2008).
36. Environmental Protection Agency. Reregistration Eligibility
Decision (RED) for Maneb. Washington, DC: Environmental
Protection Agency; 2005. (
REDs/maneb_red.pdf). (Accessed June 5, 2008).
37. Jime
´nez FJ, Mateo D, Gime
´n S. Exposure
to well water and pesticides in Parkinson’s disease: a case-
control study in the Madrid area. Mov Disord. 1992;7(2):
38. Rybicki BA, Johnson CC, Uman J, et al. Parkinson’s disease
mortality and the industrial use of heavy metals in Michigan.
Mov Disord. 1993;8(1):87–92.
39. Ritz B, Costello S. Geographic model and biomarker-derived
measures of pesticide exposure and Parkinson’s disease. Ann N
Y Acad Sci. 2006;1076:378–387.
40. Kamel F, Tanner CM, Umbach DM, et al. Pesticide exposure
and self-reported Parkinson’s disease in the Agricultural
Health Study. Am J Epidemiol. 2007;165(4):364–374.
41. Liou HH, Tsai MC, Chen CJ, et al. Environmental risk factors
and Parkinson’s disease: a case-control study in Taiwan.
Neurology 1997;48(6):1583–1588.
42. Brighina L, Frigerio R, Schneider NK, et al. Alpha-synuclein,
pesticides, and Parkinson disease: a case-control study. Neu-
rology. 2008;70(16):1461–1469.
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... Thus "equity-oriented policies about access to healthcare resources" are critical (Lix, et al., 2010, p. 335). Studies suggest a link between PD, rural living and pesticide exposure, especially among younger people (Costello, Cockburn, Bronstein, Zhang, & Ritz, 2009;Narayan, S., et al., 2013;Wang, Cockburn, Ly, Bronstein, & Ritz, 2014). Costello, et al. (2009) argue that "the critical window of exposure to toxicants may be years before the onset of motor symptoms which lead to diagnosis" (p. ...
... Studies suggest a link between PD, rural living and pesticide exposure, especially among younger people (Costello, Cockburn, Bronstein, Zhang, & Ritz, 2009;Narayan, S., et al., 2013;Wang, Cockburn, Ly, Bronstein, & Ritz, 2014). Costello, et al. (2009) argue that "the critical window of exposure to toxicants may be years before the onset of motor symptoms which lead to diagnosis" (p. 922). ...
... Environmental exposures of agrochemicals have neurotoxic effects and have been evidenced in the pathogenesis of neuro diseases such as Parkinson's. Several reports have shown overwhelming evidence of agrochemicals exposure in the development of Parkinson's disease (Corringan et al., 2000;Costello et al., 2009). Paraquat is a herbicide with chemical name 1. 10-dimethyl -4, 40-bipyridium is also a structural analogue to another neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) leading to parkinsons's (Hertzman et al., 1990;Li et al., 2005;Liou et al., 1997;Peng et al., 2005). ...
Full-text available
Pesticides and herbicides are being used worldwide to meet the food needs of the growing population and tackle the negative effects of climate change in agriculture. These agrochemicals find its way through water into our water bodies and food consumed on a daily basis. The active principle is usually assessed for toxicity and safe limits of tolerance determined by toxicology regulatory bodies. However, lack of good farming practices leads to overuse and alarming levels of these chemicals to be introduced into our ecosystem affecting humans and all life. Even though the active principle may be tolerable there have reports where the formulations used to prepare agrochemicals inadvertently increase the potency and toxicity of the preparations. Assessment of genotoxicity of agrochemicals therefore becomes of utmost importance before introducing them into the fields. Toxicity effects may be immediate, leading to massive cell death and or organ dysfunction or lead to DNA damages and epigenetic changes which manifest symptoms over time in the lifetime of an individual. Changes in DNA also lead to horizontal transfer of toxic responses in progeny. This article discusses the various tests available for toxicity testing for agrochemicals and their ability in damage detection.
... L'environnement joue un rôle majeur dans le développement de la maladie (Ascherio and Schwarzschild, 2016). Des disparités géographiques sont retrouvées et les zones les plus impactées sont : les zones à forte ruralité, induisant une exposition prolongée à des produits chimiques comme le paraquat, un herbicide, le maneb, un fongicide (Costello et al., 2009;Liou et al., 1997), ou la roténone, un pesticide (Betarbet et al., 2000) ; et les zones industrielles impliquant une exposition à des solvants organiques et des métaux lourds (Zayed et al., 1990), augmentant la pollution globale de l'environnement. Ces toxines environnementales induisent un dysfonctionnement mitochondrial et une production d'espèces radicalaires aboutissant à une augmentation du stress oxydatif et à la mort neuronale (figure 2). ...
Mon travail de thèse porte sur l’étude des troubles du contrôle des impulsions (TCI) induits après la prise de traitement aux agonistes dopaminergiques dans le cadre de la maladie de Parkinson (MP). Cette stratégie pharmacologique permet une restauration des déficits moteurs de la MP mais engendre ces effets secondaires après quelques mois à quelques années de traitements. Les études que j’ai menées avaient pour but d’explorer l’impact d’une dégénérescence dopaminergique de la voie nigrostriée et d’un traitement chronique au pramipexole (agoniste dopaminergique D3/D2) sur différents comportements. De ce fait, le premier axe de ma thèse est focalisé sur l’étude de la flexibilité cognitive dans un modèle de rat de MP. J’ai ainsi mis en évidence une susceptibilité individuelle quant à l’effet délétère de la dégénérescence dopaminergique et du pramipexole sur cette fonction exécutive, les animaux caractérisés comme flexibles étant les plus impactés. D’autre part, il n’existe pas de modèle de TCI courant, reproductible et facile à mettre en place. Le second axe de mon travail a donc été d’en générer un en se basant sur différents tests comportementaux, spontané (l’amassement de nourriture) ou opérant (le Post-Training Signal Attenuation). Nous n’avons pas mis en évidence d’impact cumulé de la dégénérescence dopaminergique et du traitement chronique au pramipexole dans le test d’amassement de nourriture. En revanche, une augmentation de l’interaction avec la nourriture est induite par le traitement, chez les individus contrôles et lésés. Le test opérant de PTSA s’est révélé plus discriminant. Effectivement, les animaux dénervés dans la voie nigrostriatale et sous traitement chronique au pramipexole sont ceux qui réalisent le plus d’essais non complétés dans la phase d’extinction du signal bien que cet effet soit modeste. Par la suite, l’implication du cortex orbitofrontal dans les fonctions exécutives et son désengagement après dénervation nigrostriatale et traitement au pramipexole nous a amené à étudier la boucle associative dans la voie cortex orbitofrontal vers le striatum dorsomédian. Des travaux antérieurs sur les boucles motrices ont mis en évidence des déficits de plasticité synaptique dans le cadre des dyskinésies et nous avons cherché à faire le parallèle avec de possibles altérations de la plasticité synaptique dans les boucles associatives dans le cadre des effets secondaires non moteurs que sont les TCI. Pour finir, ce dernier axe de ce travail s’est donc basé sur l’étude électrophysiologique des paramètres de plasticité synaptique dans la voie cortex orbitofrontal et striatum dorsomédian. Cette étude nous a permis de mettre en évidence une inversion de plasticité induite par la lésion de la voie nigrostriée ainsi que par le traitement au pramipexole tandis que la combinaison des deux ne restaure pas la plasticité synaptique normale. Nos travaux ont donc permis de renforcer nos connaissances sur la physiopathologie des effets secondaires non moteurs induits par le traitement au pramipexole en identifiant des facteurs de risques individuels comme le niveau prémorbide de fonctions exécutives. En effet, les performances prémorbides de flexibilité cognitive détermineraient l’impact de la lésion et du traitement. Cependant, ces résultats sont encore à étayer et le développement d’un modèle animal reproduisant les TCI observés chez les patients reste un objectif à atteindre. Nous avons effectivement obtenu des résultats différents sur l’étude des comportements spontanés et opérants avec respectivement des effets du pramipexole seul et des effets combinés de la lésion et du traitement. De plus, notre investigation électrophysiologique a permis de mettre en évidence un impact identique de la lésion, du pramipexole, et de la lésion combinée au traitement au pramipexole sur les boucles associatives médiée par la voie cortex orbitofrontal / striatum dorsomédian, visualisé par un défaut de plasticité synaptique.
... The interest in using paraquat as a neurotoxin to model PD started since its discovery due to its similarity in terms of its molecular structure and biochemistry with 1-methyl-4-phenylpyridinium (MPP + ), the active metabolite of MPTP, a neurotoxin that can induce PD-like features in animal models and humans [11]. For many years, studies have demonstrated that individuals exposed to paraquat had a higher risk of developing PD [12][13][14]. In this article, we will collate evidence of paraquat exposure in relation to PD and discuss paraquat-induced alterations at both cellular and molecular levels. ...
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Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by the cardinal features of tremor, bradykinesia, rigidity, and postural instability, in addition to other non-motor symptoms. Pathologically, PD is attributed to the loss of dopaminergic neurons in the substantia nigra pars compacta, with the hallmark of the presence of intracellular protein aggregates of α-synuclein in the form of Lewy bodies. The pathogenesis of PD is still yet to be fully elucidated due to the multifactorial nature of the disease. However, a myriad of studies has indicated several intracellular events in triggering apoptotic neuronal cell death in PD. These include oxidative stress, mitochondria dysfunction, endoplasmic reticulum stress, alteration in dopamine catabolism, inactivation of tyrosine hydroxylase, and decreased levels of neurotrophic factors. Laboratory studies using the herbicide paraquat in different in vitro and in vivo models have demonstrated the induction of many PD pathological features. The selective neurotoxicity induced by paraquat has brought a new dawn in our perspectives about the pathophysiology of PD. Epidemiological data have suggested an increased risk of developing PD in the human population exposed to paraquat for a long term. This model has opened new frontiers in the quest for new therapeutic targets for PD. The purpose of this review is to synthesize the relationship between the exposure of paraquat and the pathogenesis of PD in in vitro and in vivo models.
... Several studies have reported that exposure to environmental toxins, for instance, solvents (trichloroethylene (TCE) [54,55], carbon tetrachloride [55], and perchloroethylene (PERC) [55]), pesticides (paraquat [56], rotenone [56], and dieldrin [57]), fungicide (maneb) [58], mercury (Hg) [59], Fe [59], Cu [59], lead (Pb) [59], manganese (Mn) [59], and mitochondrial poison/neurotoxin1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) [60], is strongly linked to an escalated susceptibility of PD expansion. The MPTP-instigated PD model appears to be one of the most important and beneficial models of such a debilitating malady in animals and cell cultures, which is distinguishable from humanassociated PD in the context of etiology. ...
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Parkinson's disease (PD) is a complicated and incapacitating neurodegenerative malady that emanates following the dopaminergic (DArgic) nerve cell deprivation in the substantia nigra pars compacta (SN-PC). The etiopathogenesis of PD is still abstruse. Howbeit, PD is hypothesized to be precipitated by an amalgamation of genetic mutations and exposure to environmental toxins. The aggregation of α-synucelin within the Lewy bodies (LBs), escalated oxidative stress (OS), au-tophagy-lysosome system impairment, ubiquitin-proteasome system (UPS) impairment, mitochon-drial abnormality, programmed cell death, and neuroinflammation are regarded as imperative events that actively participate in PD pathogenesis. The central nervous system (CNS) relies heavily on redox-active metals, particularly iron (Fe) and copper (Cu), in order to modulate pivotal operations , for instance, myelin generation, synthesis of neurotransmitters, synaptic signaling, and con-veyance of oxygen (O2). The duo, namely, Fe and Cu, following their inordinate exposure, are viable of permeating across the blood-brain barrier (BBB) and moving inside the brain, thereby culminating in the escalated OS (through a reactive oxygen species (ROS)-reliant pathway), α-synuclein ag-gregation within the LBs, and lipid peroxidation, which consequently results in the destruction of DArgic nerve cells and facilitates PD emanation. This review delineates the metabolism of Fe and Cu in the CNS, their role and disrupted balance in PD. An in-depth investigation was carried out by utilizing the existing publications obtained from prestigious medical databases employing particular keywords mentioned in the current paper. Moreover, we also focus on decoding the role of metal complexes and chelators in PD treatment. Conclusively, metal chelators hold the aptitude to elicit the scavenging of mobile/fluctuating metal ions, which in turn culminates in the suppression of ROS generation, and thereby prelude the evolution of PD.
Mitochondria are a dynamic organelle of the cell involved in the various biological processes. Mitochondria are the site of the adenosine triphosphate (ATP) production, electron transport chain (ETC), oxidation of fatty acids, tricarboxylic acid (TCA), and cellular apoptosis. Besides these, mitochondria are the site of production of reactive oxygen species (ROS), which further disrupts the normal functioning of this organelle also making mitochondria itself as an important target of oxidative stress. Thus, mitochondria serve as an important target in the process of neurodegeneration. In the present chapter, the authors describe mitochondria and its functioning, dynamics, and the mitochondrial dysfunction in aging and neurodegenerative disorders (NDs).
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Parkinson’s disease (PD) is the second most common age-associated neurodegenerative disorder and is characterized by progressive loss of dopamine neurons in the substantia nigra. Peripheral immune cell infiltration and activation of microglia and astrocytes are observed in PD, a process called neuroinflammation. Neuroinflammation is a fundamental response to protect the brain but, when chronic, it triggers neuronal damage. In the last decade, central and peripheral inflammation were suggested to occur at the prodromal stage of PD, sustained throughout disease progression, and may play a significant role in the pathology. Understanding the pathological mechanisms of PD has been a high priority in research, primarily to find effective treatments once symptoms are present. Evidence indicates that early life exposure to neuroinflammation as a consequence of life events, environmental or behaviour factors such as exposure to infections, pollution or a high fat diet increase the risk of developing PD. Many studies show healthy habits and products that decrease neuroinflammation also reduce the risk of PD. Here, we aim to stimulate discussion about the role of neuroinflammation in PD onset and progression. We highlight that reducing neuroinflammation throughout the lifespan is critical for preventing idiopathic PD, and present epidemiological studies that detail risk and protective factors. It is possible that introducing lifestyle changes that reduce neuroinflammation at the time of PD diagnosis may slow symptom progression. Finally, we discuss compounds and therapeutics to treat the neuroinflammation associated with PD.
Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD) are neurodegenerative disorders characterized by progressive structural and functional loss of specific neuronal populations, protein aggregation, an insidious adult onset, and chronic progression. Modeling AD, PD, and HD in animal models is useful for studying the relationship between neuronal dysfunction and abnormal behaviours. Animal models are also excellent tools to test therapeutic approaches. Numerous genetic and toxin-induced models have been generated to replicate these neurodegenerative disorders. These differ in the genetic manipulation employed or the toxin used and the brain region lesioned, and in the extent to which they mimic the neuropathological and behavioral deficits seen in the corresponding human condition. Each model exhibits unique advantages and drawbacks. Here we present a comprehensive overview of the numerous AD, PD, and HD animal models currently available, with a focus on their utilities and limitations. Differences among models might underlie some of the discrepancies encountered in the literature and should be taken into consideration when designing new studies and testing putative therapies.
Parkinson's disease, as well as other neurodegenerative disorders, are primarily characterized by pathological accumulation of proteins, inflammation, and neuron loss. Although there are some known genetic risk factors, most cases cannot be explained by genetics alone. Therefore, it is important to determine the environmental factors that confer risk and the mechanisms by which they act. Recent epidemiological studies have found that exposure to air pollution is associated with an increased risk for development of Parkinson's disease, although not all results are uniform. The variability between these studies is likely due to differences in what components of air pollution are measured, timing and methods used to determine exposures, and correction for other variables. There are several potential mechanisms by which air pollution could act to increase the risk for development of Parkinson's disease, including direct neuronal toxicity, induction of systemic inflammation leading to central nervous system inflammation, and alterations in gut physiology and the microbiome. Taken together, air pollution is an emerging risk factor in the development of Parkinson's disease. A number of potential mechanisms have been implicated by which it promotes neuropathology providing biological plausibility, and these mechanisms are likely relevant to the development of other neurodegenerative disorders such as Alzheimer's disease. This field is in its early stages, but a better understanding of how environmental exposures influence the pathogenesis of neurodegeneration is essential for reducing the incidence of disease and finding disease-modifying therapies. © 2022 International Parkinson and Movement Disorder Society.
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Parkinson’s disease prevalence rates were examined for the Province of Alberta by age, sex and census division. Using the claims administrative data from the Alberta Health Care Insurance Plan, a cohort of all registered individuals (2.4 million) was extracted and followed for the five year period, April 1, 1984 to March 31, 1989. No new members were added to the cohort and an attrition rate averaging 6% per year was observed. The overall crude prevalence rates of 248.9 and 239.8 per 100,000 population were noted for males and females respectively. Both sexes were found to have a statistically significant variation across Alberta’s 19 census divisions. For males, examination of standardized morbidity ratios found a low risk of Parkinson’s disease associated with five census divisions, of which two contained Alberta’s two largest cities. An excess risk was associated with four primarily rural census divisions. Females, on the other hand, had a low risk associated with one rural census division and excess risk in four census divisions. The uneven distribution within Alberta offers support for an environmental theory of etiology which may be associated with rural living.
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Background The process of geocoding produces output coordinates of varying degrees of quality. Previous studies have revealed that simply excluding records with low-quality geocodes from analysis can introduce significant bias, but depending on the number and severity of the inaccuracies, their inclusion may also lead to bias. Little quantitative research has been presented on the cost and/or effectiveness of correcting geocodes through manual interactive processes, so the most cost effective methods for improving geocoded data are unclear. The present work investigates the time and effort required to correct geocodes contained in five health-related datasets that represent examples of data commonly used in Health GIS. Results Geocode correction was attempted on five health-related datasets containing a total of 22,317 records. The complete processing of these data took 11.4 weeks (427 hours), averaging 69 seconds of processing time per record. Overall, the geocodes associated with 12,280 (55%) of records were successfully improved, taking 95 seconds of processing time per corrected record on average across all five datasets. Geocode correction improved the overall match rate (the number of successful matches out of the total attempted) from 79.3 to 95%. The spatial shift between the location of original successfully matched geocodes and their corrected improved counterparts averaged 9.9 km per corrected record. After geocode correction the number of city and USPS ZIP code accuracy geocodes were reduced from 10,959 and 1,031 to 6,284 and 200, respectively, while the number of building centroid accuracy geocodes increased from 0 to 2,261. Conclusion The results indicate that manual geocode correction using a web-based interactive approach is a feasible and cost effective method for improving the quality of geocoded data. The level of effort required varies depending on the type of data geocoded. These results can be used to choose between data improvement options (e.g., manual intervention, pseudocoding/geo-imputation, field GPS readings).
This review summarizes advances in our understanding of the biochemical events which underlie the remarkable neurotoxic action of MPTP (1-methyl-4-phenyl-1-1,2,3,6-tetrahydropyridine) and the parkinsonian symptoms it causes in primates. The initial biochemical event is a two-step oxidation by monoamine oxidase B in glial cells to MPP+ (1-methyl-4-phenylpyridinium). A large number of MPTP analogs substituted in the aromatic (but not in the pyridine) ring are also oxidized by monoamine oxidase A or B, is in some cases faster than any previously recognized substrate. Alkyl substitution at the 2'-position changes MPTP, a predominantly B type substrate, to an A substrate. Following concentration in the dopamine neurons by the synaptic system, which has a high affinity for the carrier, MPP+ and its positively charged neurotoxic analogs are further concentrated by the electrical gradient of the inner membrane and then more slowly penetrate the hydrophobic reaction site on NADH dehydrogenase. Both of the latter events are accelerated by the tetraphenylboron anion, which forms ion pairs with MPP+ and its analogs. Mitochondrial damage is now widely accepted as the primary cause of the MPTP induced death of the nigrostriatal cells. The molecular target of MPP+, its neurotoxic product, is NADH dehydrogenase. Recent experiments suggest that the binding site is at or near the combining site of the classical respiratory inhibitors, rotenone and piericidin A.
Applications of carbaryl, captan, or both were made by fixed-wing aircraft and by low-volume ground air blast sprayer to the same orchard site. Over the course of 2 years, a total of eight applications was made, four by air and four by ground equipment. The effect of two climatic parameters was evaluated. The first was under relatively calm conditions with a temperature inversion present and the second without a temperature inversion and with wind movement up to 12.9 km/h. Regardless of wind or atmosphere stability, carbaryl deposits from aerial application were found at the furthest sampling distance (500 m downwind). Ground applications under similar conditions left deposits at 150 m during a temperature inversion but provided no detectable levels at 50 m or further in the absence of an inversion. Differences between captan drift were not as clearly defined; generally, captan did not appear to drift as readily as carbaryl.
There is mounting evidence for mitochondrial involvement in neurodegenerative diseases including Alzheimer's and Parkinson's disease and amyotrophic lateral sclerosis. Mitochondrial DNA mutations, whether inherited or acquired, lead to impaired electron transport chain (ETC) functioning. Impaired electron transport, in turn, leads to decreased ATP production, formation of damaging free-radicals, and altered calcium handling. These toxic consequences of ETC dysfunction lead to further mitochondrial damage including oxidation of mitochondrial DNA, proteins, and lipids, and opening of the mitochondrial permeability transition pore, an event linked to cell death in numerous model systems. Although protective nuclear responses such as antioxidant enzymes and bcl-2 may be induced to combat these pathological changes, such a vicious cycle of increasing oxidative damage may insidiously damage neurons over a period of years, eventually leading to neuronal cell death. This hypothesis, a synthesis of the mitochondrial mutations and oxidative stress hypotheses of neurodegeneration, is readily tested experimentally, and clearly points out many potential therapeutic targets for preventing or ameliorating these diseases.
Upon cooling partially polymerized membranes may undergo a spontaneous transition to a wrinkled rigid structure. This transition is reversible: the vesicles unwrinkle upon heating. A model is presented suggesting that this transition could be the membrane equivalent of a glass transition.
An approximation of Parkinson's disease in Spain was carried out based on the data of mortality by this disease over the period 1980-1985. The annual number of deaths by Parkinson's disease as well as its distribution by sex, age groups and Spanish provinces was obtained from information published annually by the National Institute of Statistics in the Natural Movement of the Spanish Population. The global mortality rate during the period studied was of 2.14 per 100,000 inhabitants. The specific mortality rate by Parkinson's disease in males was slightly higher than that of females. A specific mortality rate was also observed by age groups being higher in the older age groups. From the point of geographical distribution, higher rates were observed in the northern provinces with respect to the south and in rural areas compared to provinces capitals. Following the analysis of the results obtained and upon comparing the findings published in other countries it was concluded that place of residence may be related to the development of Parkinson's disease. From these data new epidemiological studies are required oriented to the identification of the environmental factors which may play a role in the etiology of this entity.
Past exposure to well water and pesticides was assessed in 128 unselected Parkinson's disease (PD) patients and 256 age and sex-matched controls. All were residents in a defined urban area of Madrid, Spain. In keeping with other reports, we found that exposure to well water might be a factor associated with the likelihood of developing PD, though only prolonged exposures of 30 years or longer were significantly different between PD and controls (p less than 0.02). In contrast, past exposure to pesticides did not appear to be associated with an increased risk of developing PD. Prolonged well water drinking antedating the development of PD was not associated with early onset of the disease, nor did such cases progress to greater disability. Future case-control studies addressing prolonged well water consumption as a risk factor in PD should look for differences in the content of substances other than pesticides in the water as determined by the source of water to which patients may have been specifically exposed.
The cytotoxicity of 1-methyl-4-phenylpyridinium (MPP+) is believed to arise as a consequence of its time- and energy-dependent accumulation inside mitochondria, followed by inhibition of electron transport at Complex I of the respiratory chain. Consistent with our proposal that the accumulation of MPP+ represents a passive Nernstian transport into mitochondria in response to the transmembrane electrochemical potential gradient, tetraphenylborate (TPB-) was found to accelerate the onset of the respiratory inhibition by MPP+ on intact mitochondria. Moreover, the ultimate level of inhibition reached was unexpectedly also increased. The latter is now explained by our finding that TPB- elicits a 12-fold enhancement of MPP+ inhibition of respiration in electron transport particles. It is suggested that TPB- facilitates access of MPP+ to its intramembrane site of inhibitory action in Complex I.
Two worker-exposure and drift trials were conducted during the aerial application of paraquat to cotton in California, USA. The dermal and respiratory exposure of pilots, flaggers, and a mixer-loader was shown to be low. Dermal exposure ranged from 0.05 (pilot) to 2.39 (flagger) mg/ hr. The dermal exposure of the mixer-loader was similar to that of the pilots. No respirable paraquat was detected in the breathing zone of any worker. The highest total paraquat concentration was 26.3 µg/m3 for a flagger, which is a factor of 19 less than the TLV for total paraquat. The combined dermal and respiratory exposure of this flagger was equivalent to 19.4 mg/8hr working day. Paraquat drift concentrations decreased with increasing distance downwind of the spray application. The highest concentrations of total and respirable paraquat were 16.7 and 0.15 µg/m3 at 50 m from the application site perimeter. The respective concentrations at 1600 m downwind were 0.5 and 0.01 µg/m3. Measurement of the particle size distribution of paraquat drift showed that 0.95 to 1.96% of spray droplets was within the respirable range at all distances downwind. The highest percentage of respirable droplets was equivalent to 1.2 (µg paraquat, which was measured at 400 m downwind. Respirable fractions of 1 and 0.95% were measured at 50 and 100 m downwind, which represented 1.8 µg paraquat. There was no evidence, therefore, of a toxic hazard to pilots, ground crew, and downwind bystanders, as a consequence of the aerial application of paraquat.