Critical Review

Environmental, lifestyle, and familial/ethnic factors associated with

myeloproliferative neoplasms
Lesley A. Anderson,1 Andrew S. Duncombe,2 Maria Hughes,1 Moyra E. Mills,3 Jessica C. Wilson,1 and
Mary F. McMullin4*
Myeloproliferative neoplasms (MPNs) are characterized by overproduction of mature functional blood cells
and are often associated with an acquired genetic mutation of Janus Kinase 2V617F. The etiology of MPNs
remains unknown. The aim of this article was to review and collate all known published data investigating
environmental and lifestyle factors associated with MPNs. Medline, Embase, PubMed, Cochrane, and Web
of Science were systematically searched using terms for MPNs and observational study designs to identify
studies investigating the risk factors for MPNs published before March 2010. Of 9,156 articles identied, 19
met the selection criteria. Although the studies exhibited heterogeneity, in case denitions, study design,
and risk factors investigated, several themes emerged. A strong association was found with Jewish
descent, and with a family history of MPNs. Autoimmune conditions, specically Crohns disease, were
more common in patients with MPNs. Certain occupational groups were signicantly associated with MPNs
including occupations with potential exposure to benzene and/or petroleum. Blood donation was associ-
ated with an increased risk of polycythemia vera specically. The vast heterogeneity in studies identied as
part of this review suggests that large scale systematic assessment of etiological factors associated with
MPNs is warranted. Am. J. Hematol. 87:175182, 2012. V C 2011 Wiley Periodicals, Inc.

Introduction Despite these recent advances in the identication of gene

Myeloproliferative neoplasms (MPNs) are a group of he-
matopoietic malignancies resulting from a transformed he-
matopoietic progenitor cell. They are characterized by over-
production of mature functional blood cells. MPNs were his-
torically termed myeloproliferative disorders and have
undergone numerous amendments in classication. The
2008 World Health Organisation MPN classication groups
a number of related disorders including the classic MPNs
polycythemia vera (PV), essential thrombocythemia (ET),
and primary/idiopathic myelobrosis (PMF) [1] which will be
the focus of this review. Reported incidence rates vary from
0.02 to 2.8 per 100,000 persons [2]. However, incidence
rates are not well characterized and half of all patients are
asymptomatic at diagnosis [1]. PV and ET are indolent neo-
plasms with better prognosis (88% and 92% 3-year sur-
vival, respectively) compared to PMF which has a 63% 3-
year survival in the United States [3].
An acquired genetic mutation of Janus kinase 2
(JAK2)V617F is present in the majority of PV patients and in
approximately half of patients with ET and PMF [4]. A recent
study investigating JAK2V617F mutations in 10,507 partici-
pants of the Copenhagen City Heart Study reported an inci-
dence rate of 171 per 100,000 persons [5]. These partici-
pants had higher overall morbidity and mortality than those
who were JAK2V617F negative; however, 28% did not develop
any malignancy during the 17.6-year follow-up [5]. Numerous
other acquired mutations, for example, JAK2 exon 12 [6] and
mutations in MPL [7], CBL [8], EZH2 [9], LNK [10], TET2,
IDH1/2, ASXL1, and IKZF1 [11] have also been identied in
MPN patients. Inherited germ-line mutations have been
investigated. The 46/1 JAK2 haplotype has been identied as
a polymorphism occurring in approximately 50% of the popu-
lation and is associated with a 3.7-fold increased risk of
developing JAK2V617F associated MPNs [12]. The population
attributable risk of 46/1 JAK2 in PV patients has been esti-
mated at 28%, explaining approximately 50% of the
increased risk of PV in rst-degree relatives [12]. The GG/
CC genotype at JAK2 rs10974944 has been associated with
an almost 2.8-fold increased risk of familial MPN [13]; how-
ever, other germ-line mutations remain to be identied [14].
mutations it is likely that environmental and lifestyle factors
also play a role in the development of MPNs. However, lim-
ited research has been conducted in this area. The aim of
this review was to systematically search the literature to iden-
tify and collate information on potential environmental, life-
style, and familial/ethnic risk factors associated with MPNs.
Design and Methods
Study selection. A systematic literature search was conducted
using Ovid MEDLINE (US National Library of Medicine, Bethesda,
MD), PUBMED (US National Library of Medicine and the National Insti-
tutes of Health, Bethesda, MD), EMBASE (Reed Elsevier PLC, Amster-
dam, The Netherlands), and Web of Science (Thompson Reuters, Phil-
adelphia, USA). The search strategy included broad terms for MPNs
(including specic terms for PV, ET, and myelobrosis) and epidemio-
logical study designs (including cohort, casecontrol, and cross-sec-
tional study terms). The search did not include specic terms for
chronic myelogenous leukemia (CML) since this is considered a distinct
clinical entity. Searches included articles published until end February
2010. No language or other restrictions were imposed.
Five independent researchers initially reviewed the title and abstract
of the articles identied (LAA, MH, MM, JCW, MFMcM). Articles were
considered for inclusion if they:
1. included patients with MPNs, specically PV, ET, and/or PMF.
2. were epidemiological studies (i.e., cohort or casecontrol study
design).
3. included information on exposures/risk factors associated with
MPNs.
1
Centre for Public Health, Queens University Belfast, Northern Ireland;
2
Department of Haematology, Southampton University Hospitals Trust,
United Kingdom; 3School of Nursing and Midwifery, Queens University Bel-
fast, Northern Ireland; 4Centre for Cancer Research and Cell Biology,
Queens University Belfast, Northern Ireland
Conict of interest: Nothing to report
*Correspondence to: Mary Frances McMullin, MD, FRCPath, Haematology,
Centre for Cancer Research and Cell Biology, The Queens University Bel-
fast, 97 Lisburn Road, Belfast, BT9 7BL, United Kingdom.
E-mail: m.mcmullin@qub.ac.uk
Received for publication 30 September 2011; Accepted 30 September 2011
Am. J. Hematol. 87:175182, 2012.
Published online 11 October 2011 in Wiley Online Library (wileyonlinelibrary.com).
DOI: 10.1002/ajh.22212

V
C 2011 Wiley Periodicals, Inc.

American Journal of Hematology 175 http://wileyonlinelibrary.com/cgi-bin/jhome/35105

critical review

Observed/Expected 1.81 (95% CI 0.873.33)

Observed/Expected 2.38 (95% CI 1.144.38)

The nal articles identied were screened by two independent inves-

incidence in population of 2 per 100,000

tigators (LAA, MFMcM) to ensure all criteria were met and discrepan-

Signicant with a 5-year latency period:

cies were resolved by discussion.

120 per 100,000 compared to crude

Data extraction. Information regarding study design, study year,

[PMR 10.9 (95% CI 1.485.0)]

number of patients with MPNs, types of MPNs included, cohort/com-

Observed only in males: [SMR

Particularly non-white females:

SMR 455 (95% CI 1201,164)
parison group (number in group), exposures, and associated risk esti-

SMR 62.5 (95% CI 7.6226)

PMR 4.9 (95% CI 1.417.2)

SMR 201 (95% CI 41588)
Results

mates were extracted from the articles.

PMR 405 (not signicant)

PMR 163 (not signicant)

105 (95% CI 13378)]

Analysis. As there was signicant heterogeneity, in the denition
of cases, study design, and risk factors investigated, a meta-analysis
was not conducted. Instead, studies were grouped according to study
design (casecontrol versus cohort) and the potential factors identied
and subjected to qualitative descriptive analysis. A table summarizing
the main risk factors identied for MPNs and the strength of evidence
associated with each factor was produced.
Results
A total of 6,315 articles underwent initial screening after
exclusion of duplicates (n 5 2,841). Of the 51 full text
Polycythemia vera (n 5 4)

Polycythemia vera (n 5 2)
No cases of Myelobrosis
Myelobrosis (n 5 3)

Myelobrosis (n 5 3)

Myelobrosis (n 5 2)
articles screened 19 met the inclusion criteria. These stud-
Polycythemia vera

Polycythemia vera

ies were categorized into cohort (n 5 6) and casecontrol

observed
Outcome

(n 5 13) studies and are presented in Tables I and II,

respectively.
Family history
Four observational studies investigated family history of
MPNs [2224,26]. Najean et al. reported an excess of PV
and ET in families compared to the reference population
[22]. Landgren et al. similarly reported increased risk of
members of the meatcutters

MPN, PV, and ET in relatives of patients with MPN, PV, or

Petroleum Renery workers

36,795 active blood donors

ET [24]. Relatives with female probands had a signicantly

Poultry workers who were
Funeral service workers

of parathyroid glands
Commercial Pressmen

Patients with adenoma

union (n 5 28,900):

higher risk of MPN than those of male probands [24]. This

Cohort

was not supported in the study by Giles et al. where having

(n 5 20,169)

a son with a MPN increased the risk of MPN 50-fold [26],

(n 5 5,265)
(n  2,500)

(n 5 101)

Table II. Hemminki and Jiang reported a higher risk of PV

in patients with a parent with PV, lymphatic and myeloid
leukemia, or breast cancer [23].
No signicant associations were reported between PV
and having a parent/sibling with a cancer in any of the fol-
lowing sites: oral, stomach, colon, rectum, pancreas, lung,
Cancer incidence

cervix, endometrium, prostate, kidney, bladder, melanoma,

until 1981

until 1980

until 1986

until 1985

until 1992

until 2003
Follow-up

Mortality

Mortality

Mortality

Mortality

Mortality

skin, nervous system, connective tissue, non-Hodgkin lym-

phoma, or Hodgkin lymphoma [23].
Jewish decent
Two studies investigated Jewish decent as a risk factor
for MPNs [21,22]. Najean et al. reported that 5.8% of PV
cases were of Jewish decent compared to 3% in the refer-
19581981

19721980

19711981

19751985

19801992

19541979

ence population in France [22]. Chaiter et al. reported that

Year

81.2% of patients with MPNs in Northern Israel had Ashke-

nazi Jewish decent compared to 32.5% in the reference
population [21].
Occupation
32 USA states and District of Columbia

PMR, proportional mortality ratio; SMR, standardized mortality ratio.

Of the six cohort studies identied, signicantly higher

states and New York City (death

mortality rates from PV and/or myelobrosis were reported

certicates); National Funeral
funeral directors), USA; Nine
(Licensing boards and state
Representative cohort of USA

in poultry workers [20], commercial pressmen [15], and pe-

New York City, Long Island,
Study location

troleum renery workers [16] compared to the reference

Directors Association
petroleum reneries

populations, Table I. Funeral service workers also appeared

New Jersey, USA

Southern Stockholm

to have a higher risk of PV but this did not reach statistical

Baltimore, USA

signicance [18].
Four casecontrol studies investigated occupational
Udine, Italy

groups associated with ET [30,31] or MPNs [26,28], Table

II. Mele et al. reported an association with working with
electrical devices only [30], Table II. ET patients were also
more likely than controls to have been cooks/waiters and
TABLE I. Cohort Studies

clerks [31], Table II. Agricultural workers have been

Johnson et al., 2010 [20]
Pizzolito et al., 1997 [19]
Kaplan et al., 1986 [16]

reported to have a higher risk of developing myeloprolifera-

Hayes et al., 1990 [18]
Zoloth et al., 1986 [15]

Merk et al., 1990 [17]

tive syndromes [28]. In an Australian casecontrol study of

myelobrosis and PV combined, rural sector jobs (process
and production workers/tradesmen, metal workers, and
farmers/farm workers) were more common in these
Article

patients compared to controls [26], Table II. Other occupa-

tions investigated including professional, administrative,

176 American Journal of Hematology

 TABLE II. CaseControl Studies
Article
Jewish decent/Family history
Chaiter et al., 1992 [21]
Najean et al., 1998 [22]
American Journal of Hematology
Hemminki et al., 2001 [23]
Landgren et al., 2008
(MPN, PV, ET) [24]
Occupation/chemical exposures
Quiroga Micheo et al.,
1981 [25]
Giles et al., 1984 [26]
Lickiss et al., 1984 [27]
Pasqualetti et al., 1991 [28]
177
Study location Year Cases Controls Exposure Results
Hospital-based case 19751989 Agnogenic myeloid Jewish population (Northern Israel) Ashkenazi Jewish decent 81.2% in MPD patients compared to
series, Northern metaplasia, essential 32.5% in population
Israel throbocythemia. Urban residence 24 per 100,000 in MPD compared to
Polycythemia vera 11.5 per 100,000 in population.
(n 5 339)
France 19801990 Polycythemia vera Reference population (Iie-de-France Blood donors 21% in PV patients compared to 8% in
(n 5 842) region; Aube, Eure-et-Loir, Yonne.) reference population (Blood
Data from 1990 French census, cause Transfusion data)
of death register (1990), risk of cancer Excess of PV and ET in families 11 per 100,000 observed in PV patients
in adult population and National compared to 12 per 100,000
Transfusion Center, National Jewish expected in reference population.
Consistory, Paris Chamber of Jewish origin 5.8% in PV patients compared to 3% in
Commerce, blood donation, religion, population
occupations in region.
Sweden 19752000 PV (n 5 90170 cases Observed compared to expected rates in Parent of PV case: Breast SIR 1.61 (95%CI 1.002.38)
per year) database of all Swedes born since Lymphatic and myeloid leukemia SIR 2.52 (95%CI 1.004.73)
1932 based on age, period, PV SIR 10.9 (95%CI 3.9221.3)
residence, sex and socioeconomic
class
Sweden 19582005 Myeloproliferative 4 population-based controls matched on First degree relatives
neoplasm gender, age, birth year and county of
(n5 11,039): residence.
PV (n 5 6,217) MPN patients MPN (RR 5.6 95% CI 3.88.2)
ET (n 5 2,838) PV (RR 5.7 95% CI 3.89.1)
ET (RR 7.4 95% CI 3.714.8)
MF (n 5 1,172) PV patients MPN (RR 4.9 95% CI 3.17.8)
PV (RR 6.0 95% CI 3.311.0)
ET (RR 5.4 95% CI 2.213.2)
Not otherwise specied ET patients MPN (RR 6.8 95% CI 3.413.5)
(n 5 812) PV (RR 5.4 95% CI 2.213.1)
ET (RR 8.8 95% CI 2.624.5)
Argentina 19731980 Myeloproliferative Non-neoplastic frequency matched Petroleum P 5 0.02
disorders: CML (age, gender) from same
n 537; PV n 5 10; hospitals. N 5 603
Agnogenic myeloid
metaplasias n54
Tasmania, Australia 19721980 Myeloproliferative Electoral rolls (mandatory after Rural sector jobs (males) RR 2.25 (95% CI 1.21-3.8)
including Myelobrosis 6 months residence) (n 5 530) Process and production workers/ RR 2.76 (95% CI 1.54-5.72)
(n 5 28), Polycythemia tradesmen
vera (n 5 46) Metal workers (>55 years) RR 3.0 (95% CI 1.0410.6)
Farmers/farm workers (male) RR2.57 (95% CI 1.355.44)
First degree relative (males) RR5.17 (P < 0.05)
Brother with MP (males) RR 14.81 (P < 0.01)
Son with MP (males) RR 50.00 (P < 0.05)
First degree relative (females) RR 5.21 (P < 0.01
Daughter with MP (females) RR 5.21 (P < 0.05)
Tasmania, Australia 19721980 Myeloproliferative Electoral rolls (mandatory after Rural residence (males: 05 years) RR 2.32 (95% CI 1.293.78)
including 6 months) (n 5 530) Rural residence (females: 05 yrs) RR 1.43(95% CI 0.523.19)
Myelobrosis (n 5 regional areas investigateda
28), Polycythemia
rubra vera (n 5 46)
Italy - Myeloproliferative Matched controls from same geographic Agricultural work Increased risk, P < 0.05
syndromes (n 5 44) area, affected with medical diseases
except cancer/congenital diseases
(n 5 620)
critical review
178
TABLE II. Continued

Article Study location Year Cases Controls Exposure Results

critical review

Terreros et al., 1997 [29] Argentina 19931995 Myeloproliferative 163 age and sex matched controls from Some environmental/ occupational OR 0.95 (95%CI 0.118.00)
syndrome (n 5 9) a public hospital exposure
Benzene OR 46.6 (95% CI 2.022761)
Mele et al., 1996 [30] Italy 19861990 Essential Hospital outpatients with no Shoemaker AOR 2.7 (95% CI 0.516.0)
thrombocythemia haematologic disorders (n 5 156) Agricultural worker AOR 1.0 (95% CI 0.34.0)
(n 5 39) Electrical worker 5.1% cases, 0% controls (P 5 0.004)
Tuff house (>9 years) AOR 5.1 (95% CI 1.222.1)
Dark hair dye (>10 years) AOR 5.3 (95% CI 1.419.9)
No signicant associations were
observed with other occupational
groups, diagnostic/therapeutic X-rays,
family history of malignancy, use of
herbicides and pesticides, residence
in countryside, contact with pet and/or
farm animals, smoking or drinking.
Falcetta et al., 2003 [31] Italy 19902000 Essential Random population controls (n 5 280) Cooks/waiters OR 4.96 (95% CI 1.5916.9)
thrombocytemia Clerks OR 2.63 (95% CI 1.534.51)
(n 5 93) Hairdressers OR 5.10 (95% CI 0.8231.4)
Nurses OR 3.75 (95% CI 0.8019.4)
Farmers OR 1.74 (95% CI 0.843.56)
Electricians OR 1.42 (95% CI 0.483.78)
Photographers OR innity
Anderson et al., 2009 [32] SEER-Medicare USA 2001/2002 Polycythemia vera and Frequency matched, randomly selected Autoimmune hemolytic anemia OR 11.9 (95% CI 4.7230.2)
chronic Medicare subjects without cancer Localized scleroderma OR 2.34 (95% CI 1.025.37)
myeloproliferative (n 5 160 086) Crohns disease OR 2.18 (95% CI 1.014.71)
disease (n 5 1,017)
Kristinsson et al., 2010 [33] Sweden 19582005 Myeloproliferative 4 population-based controls matched on Myeloproliferative neoplasm
neoplasm gender, age, birth year and county of Any autoimmune disease
(n 5 11,039) residence. Idiopathic thrombocytopenic purpura
PV (n 5 6,217) Crohns OR 1.2 (95% CI 1.01.3)
ET (n 5 2,838) Polymyalgia rheumatica OR 2.9 (95% CI 1.27.2)
MF (n 5 1,172) Giant cell arteritis OR 1.8 (95% CI 1.13.0)
NOS (n 5 812) Reiters syndrome OR 1.7 (95% CI 1.22.5)
Aplastic anemia OR 5.9 (95% CI 2.414.4)
Polycythemia vera OR 15.9 (95% CI 1.8142.0)
Giant cell arteritis OR 7.8 (95% CI 3.716.7)
Aplastic anemia
Essential thrombocythemia OR 3.9 (95% CI 1.015.8)
Any autoimmune disease OR 5.9 (95% CI 1.721.0)
Crohns
Polymyalgia rheumatica OR 1.2 (95% CI 1.01.6)
Giant cell arteritis OR 3.3 (95% CI 1.37.9)
Primary myelobrosis OR 2.3 (95% CI 1.34.2)
Giant cell arteritis OR 7.8 (95% CI 1.442.4)
Psoriasis
OR 31.7 (95% CI 4.0253.6)
OR 3.3 (95% CI 1.010.8)

AOR, adjusted odds ratio; OR, odds ratio; RR, relative risk; PV, polycythemia vera; ET, essential thrombocythemia; MF, myelobrosis; MPD5myeloproliferative disorder.

American Journal of Hematology


clerical, sales, mining, transportation/communication, serv-
ice industries, foundry workers, food and beverage workers,
and hairdressers were not associated with myeloprolifera-
tive disorders [26]. Pasqualetti et al. reported no signicant
association between some environmental/occupational ex-
posure" and myeloproliferative syndrome [28]. Najean et al.
also investigated occupation but there was no control group
or population statistics for comparison [22].
Chemical exposure
Chemical exposure was investigated by ve casecontrol
studies [25,2830]. Terreros et al. reported an almost 50-
fold increased risk of myeloproliferative syndrome in per-
sons exposed to benzene [29]. Petroleum was also report-
edly associated with an increased risk of myeloproliferative
disorders including CML [25], Table II. Conversely, Pasqua-
letti et al. reported that exposure to a number of chemicals,
including pesticides, fertilizers, paints, and aromatic hydro-
carbons, e.g., benzene were not associated with myelopro-
liferative syndromes [28]. Mele et al. reported that using
dark hair dye for more than 10 years was signicantly asso-
ciated with an increased risk of ET [30]. However, in a
more recent publication no signicant associations were
reported between ET and the use of hair dyes, pesticides,
solvents, or dichlorodiphenyltrichloroethane [31].
Residence
In an Australian study, males living in a rural residence
for 05 years had a higher risk of myeloproliferative disor-
ders compared to controls [27], Table II. Interestingly, in an
Italian casecontrol study living in a tuff house (a house
made from a volcanic porous material that emits gamma
radionucleotides and radon) for more than 9 years was
more common in ET patients than controls [30], Table II.
Medical conditions
A number of autoimmune conditions have been investi-
gated in association with MPNs [32,33], specically PV, ET,
and PMF [33]. Only those reaching statistical signicance
are reported in Table II. Crohns disease was associated
with myeloproliferative disorders in both the Swedish [33]
and USA studies [32], Table II. In the Swedish study, only
giant cell arteritis was associated with PV, ET, and PMF
[33], Table II. In the cohort study by Pizzolito et al. males
with adenoma of the parathyroid gland had an increased
risk of PV [19], Table I.
Blood donation
In a cohort of active blood donors from Southern Stock-
holm, the incidence of PV was higher than expected more
than 5 years after blood donation [17], Table I. Blood
donors in France were also reported to have higher rates
of PV compared to the reference population (21% vs. 8%,
respectively) [33], Table II.
Discussion
This systematic review of the literature identied a
diverse range of studies investigating potential environmen-
tal, lifestyle, and familial/ethnic risk factors associated with
MPNs. However, it was clear that there was signicant het-
erogeneity in the denition of cases, study design, and risk
factors investigated. Additionally, several of the studies
were limited by small sample sizes limiting their power to
detect modest associations between potential risk factors
and MPNs. Despite this several potential etiological themes
emerged, Table III. The strongest evidence was for an
increased risk of MPNs in those with a family history of
MPNs and those of Jewish decent. There was some evi-
dence to suggest an association between Crohns disease
and MPNs but the nature of this association requires fur-
ther investigation. Several occupational groups were investi-
gated across studies but there was limited consensus of
American Journal of Hematology
critical review
opinion as to which occupations posed the highest risk of
developing MPNs.
Inherited germ-line mutations including the 46/1 JAK2
haplotype [12] and the GG/CC genotype at JAK2
rs10974944 [13] have been identied in patients with
MPNs. Case studies have reported familial clustering of PV
[3437] and ET [3841]. There have also been strong
associations reported between Jewish decent and risk of
MPNs but only to observational studies were identied
[21,22]. Although further investigation of other potential
germline mutations is warranted, shared environmental and
lifestyle factors may contribute to the excess risk observed
in patients with a family history of MPNs or of Jewish
decent.
Autoimmune conditions have been associated with the
development of myeloid neoplasms, including MPNs
[32,33]. Interestingly, both the Swedish and USA studies
identied reported an association between Crohns disease
and MPNs [32,33]. A single nucleotide polymorphism in
JAK2 (rs10758669) has been identied in both PV patients
[42] and patients with Crohns disease [43], suggesting a
shared somatic mutation. Giant cell arteritis was associated
with PV, ET, and PMF in the Swedish study even when the
5-year period preceding diagnosis of MPN was excluded
[33]. Only a few case reports have been published in the lit-
erature [44,45]. It has been suggested that ophthalmic cir-
culation may be affected by high platelet counts and could
explain an increased risk of giant cell arteritis in patients
with MPN [45]. Based on the evidence to date, it is not
possible to determine whether autoimmune conditions are
risk factors for MPNs or co-occur through similar pathways.
The majority of studies in this review investigating occu-
pational exposures, including commercial pressmen [15],
shoe makers [30], and poultry workers [20] and MPNs sug-
gested benzene as a potential contributing factor. Addition-
ally, an excess risk of myelobrosis has been reported in
motor vehicle drivers (P < 0.05) and workers in car trans-
port (P < 0.05), other road transport (P < 0.05) and railway
sectors (P < 0.05) [46] which the authors attribute to ben-
zene exposure from petrol. Wolff also reported a signicant
correlation between car ownership and excess risk of mye-
loproliferative disease in a UK-based ecological study [47].
However, only one small study (n 5 9) in the review speci-
cally investigating benzene exposure and myeloproliferative
syndrome demonstrated a signicant association [29]. Con-
versely, Pasqualetti et al. reported no association between
aromatic hydrocarbons, which contain one or more ben-
zene rings, and MPNs in a study of 44 MPN patients [28].
Benzene is primarily produced from petroleum which has
also been associated with an increased risk of PV, ET [16]
and myeloproliferative disorders [25]. Gall rst reported a
case of myeloid metaplasia (now termed PMF) in a patient
with benzene poisoning in 1938 [48]. Subsequently, ben-
zene has been reported to be associated with an increased
risk of PMF in numerous case reports [46,4953]. The
effects of benzene on risk of developing MPNs require fur-
ther investigation collecting information on levels of expo-
sure, time, and duration of exposure and use of protective
equipment.
Agricultural work has been associated with MPNs in
some [26,28], but not all [30], studies. Exposure to carcino-
genic substances varies by type and location of farming
causing difcultly in the identication of key carcinogenic
compounds. The studies identied in the review were lim-
ited by small sample sizes limiting their power to detect sig-
nicant associations and the ability to conduct stratied
analyses based on type of farming or exposure.
Radiation exposure is strongly associated with leukemia
[54]. Mele et al. reported an increased risk of ET in per-
179
critical review
TABLE III. Summary of Environmental and Lifestyle Factors Associated With Myeloproliferative Neoplasms (MPNs) Including Polycythemia Vera (PV),
Essential Thrombocythemia (ET), and Primary Myelobrosis (PMF)

Studies demonstrating no Strength of evidence

Studies showing excess risk excess risk of MPN (-5 none,* some, **5 weak,
Risk factor of MPN (MPN group) (MPN group) *** 5 moderate, **** 5 strong)

Jewish ancestry/Family history

Jewish ancestry Najean et al., 1998 (PV) [22] ****
Chaiter et al., 1992 (PV, ET) [21]
Family history Najean et al., 1998 (PV) [22] Mele et al., 1996 [30] ****
Hemminki et al., 2001 (PV) [23]
Landgren et al., 2008 (MPN, PV, ET) [24]
Giles et al., 1984 (PV/PMF) [26]
Occupations
Commercial pressmen Zoloth et al., 1986 (PMF) [15] *
Petroleum renery workers/petroleum Kaplan et al., 1986 (PV, PMF) [16] *
Quiroga Micheo et al., 1980 (MPN) [25]
Funeral service workers Hayes et al., 1990 (PV, PMF) [18] -
Poultry workers Pizzolito et al., 1997 (PV) [19] *
Johnson et al., 2010 (PMF) [20]
Cooks/waitors Falcetta et al., 2003 (ET) [31] *
Clerks Falcetta et al., 2003 (ET) [31] *
Hair dressers Falcetta et al., 2003 (ET) [31] -
Mele et al., 1996 (ET) [30]
Nurses Falcetta et al., 2003 (ET) [31] -
Photographers Falcetta et al., 2003 (ET) [31] *
Child care worker Mele et al., 1996 (ET) [30] -
Shoemaker Mele et al., 1996 (ET) [30] -
Electrical worker Falcetta et al., 2003 (ET) [31] -
Mele et al., 1996 (ET) [30]
Agricultural work Pasqualetti et al., 1991 (MPN) [28] Falcetta et al., 2003 (ET) [31] *
Giles et al., 1984 (PV/PMF) [26] Mele et al., 1996 (ET) [30]
Metal workers Giles et al., 1984 (PV/PMF) [26] *
Process/production workers Giles et al., 1984 (PV/PMF) [26] *
Painter Mele et al., 1996 (ET) [30] -
Benzene/Hydrocarbons Terreros et al., 1997 (MPN) [29] Pasqualetti et al., 1991 (MPN) [28] *
Herbicides/pesticides/solvents Falcetta et al., 2003 (ET) [31] -
Mele et al., 1996 (ET) [30]
Radiation Najean et al., 1998 (PV) [22] -
Mele et al., 1996 (ET) [30]
Autoimmune conditions
Autoimmune hemolytic anemia Anderson et al., 2009 (MPN) [32] *
Localised scleroderma Anderson et al., 2009 (MPN) [32] *
Crohns disease Anderson et al., 2009 (MPN) [32] **
Idiopathic thrombocytopenic purpura Kristinsson et al., 2010 (MPN) [33] *
Polymyalgia rheumatic Kristinsson et al., 2010 (MPN, ET) [33] Anderson et al, 2009 (MPN) [32] *
Giant cell arteritis Kristinsson et al., 2010 (MPN, PV, ET, PMF) [33] Anderson et al, 2009 (MPN) [32] *
Reiters syndrome Kristinsson et al., 2010 (MPN) [33] *
Aplastic amenia Kristinsson et al., 2010 (MPN, PV, ET) [33] *
Psoriasis Kristinsson et al., 2010 (PMF) [33] Anderson et al, 2009 (MPN) [32] *
Other
Blood donation Merk et al., 1990 (PV) [17] *
Najean et al., 1998 (PV) [22]
Patients with adenoma of parathyroid glands Pizzolito et al., 1997 [19] *
Rural residence Lickiss et al., 1984 (PV/PMF) [27] Chaiter et al., 1992 (PV/ET) [21] *
Pasqualetti et al., 1991 (MPN) [28]
Mele et al., 1996 [30]
Alcohol/tobacco Pasqualetti et al., 1991 (MPN) [28] -
Mele et al., 1996 [30]
Dark hair dye use Mele et al., 1996 (ET) [30] Falcetta et al., 2003 (ET) [31] *
Contact with animals Mele et al., 1996 (ET) [30] -

sons living in tuff houses which contain gamma-emitting ra-
dionuclides [30]. Additionally, PV has been reported in four
cases (two conrmed, two suspected) exposed to radiation
during a nuclear weapons test in 1981, which exceeded the
expected number of cases [55]. However, Najean et al.
concluded that radiation exposure was not associated with
PV in a cohort of 842 cases [22]. Although no comparison
group was available, only four PV cases had frequent radia-
tion for pulmonary tuberculoisis and six had occupations
with potential radiaiton exposure [22]. Additionally, in Eng-
land and Wales no correlation was observed between ra-
don levels and myeloproliferative disorders in an ecological
study [56]. The studies to date do not provide any conclu-
sive evidence that radiation exposure is a strong risk factor
for MPNs. The heterogeneity of exposure both within and
between occupations may mask some potential associa-
tions between occupational exposures and risk of MPNs.
In-depth investigation of occupational exposures, duration
of exposure, usage of protective equipment, and other
health and safety measures undertaken may help to deter-
mine which occupational exposures are truly associated
with an increased risk of MPNs.
A higher incidence of PV has been reported in blood
donors [17,22]. There are a number of potential explana-
tions for this apparent association. Firstly, increased blood
screening in donors may lead to a diagnosis of an other-
wise asymptomatic MPN. Secondly, patients with high full
blood counts may be more likely to be deemed suitable for
blood donation. Finally, blood donation may lead to
increased erythrocyte proliferation which may be associated
with an increased risk of PV. Retrospective large scale
investigation of blood donation in patients with PV and

180 American Journal of Hematology


other MPNs, including blood counts, frequency, and dura-
tion of blood donation, may shed further light on the poten-
tial mechanisms behind this association.
This systematic review included broad search terms for
MPNs and observational study designs to identify as many
published articles as possible. Foreign language articles
were included in the study and multiple databases were
searched. In addition, the authors also reviewed the refer-
ence lists of identied articles for further studies not identi-
ed as part of the review. Unfortunately, it is not possible to
preclude the possibility that studies were not identied if
MPNs were one of a number of conditions investigated and
not reported on in the main article.
Despite recent advances in the identication of somatic
and germline mutations in patients with MPNs, environmen-
tal and lifestyle risk factors are likely to play a large role in
the development of these conditions. Evidence collated as
part of this review suggests that some occupational expo-
sures may be associated with MPNs. However, more in-
depth investigation of levels and duration of exposure and
use of protective equipment are required. The relation
between autoimmune conditions and MPNs requires further
investigation to determine whether shared genetic path-
ways are responsible for the excess risk reported in large
population-based studies and specically for the associa-
tion with Crohns disease. The limited number and hetero-
geneity of published studies investigating other environmen-
tal and lifestyle risk factors suggest that a well-designed,
large coordinated epidemiological investigation should be
conducted.
Author Contributions
LAA, ASD, and MFMcM designed the study. All authors
were involved in the review of titles and abstracts, com-
mented on article drafts, and approved the nal version of
the manuscript.
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