Upload
freddy-a-manayay
View
224
Download
0
Embed Size (px)
Citation preview
7/27/2019 ARPH Schottenfeld Final
1/25
Current Perspective on theGlobal and United StatesCancer Burden Attributable
Lifestyle and EnvironmentaRisk FactorsDavid Schottenfeld,1,2,3Jennifer L. Beebe-DimmPatricia A. Buffler,7 and Gilbert S. Omenn1,3,4
1School of Public Health, 2Department of Epidemiology, 3Medical School, DepartmInternal Medicine, 4Departments of Computational Medicine and Bioinformatics,Human Genetics, University of Michigan, Ann Arbor, Michigan 48109;email: [email protected], [email protected]
5Karmanos Cancer Institute, Division of Population Studies and Disparities Researc6
Department of Oncology, Wayne State University, Detroit, Michigan 48201;email: [email protected]
7School of Public Health, Department of Epidemiology, University of California, BCalifornia 94720; email: [email protected]
Annu. Rev. Public Health 2013. 34:97117
The Annual Review of Public Health is online atpublhealth.annualreviews.org
This articles doi:10.1146/annurev-publhealth-031912-114350
Copyright c 2013 by Annual Reviews.All rights reserved
Keywords
cancer epidemiology, cancer prevention, population attributable
fractions, multistep carcinogenesis
Abstract
Our objective is to provide a current perspective on the avoidable c
of global and US cancer incidence and mortality. Cancer registrybincidence patterns, population behavioral risk-factor survey data
systematic reviews of epidemiologic studies are the basis for estim
of relative risk, the prevalence of exposures to various lifestyle and
vironmental risk factors, and their impact expressed as populatio
tributable fractions(PAFs). Of thetotal 59 million globaldeathsin 2
1213% were attributed to cancer. The increasing burden of can
in low- and middle-income countries (LMICs) is attributable in pa
increasing urbanization, expansion of the adult population at risk
increasing or persistent exposures to infectious agents, tobacco, an
etary deficiencies. Attributable fractions for lifestyle and environm
risk factors are summarized for the United States, the United Kingand France. Assuming minimal overlap in the distribution of risk fa
in the population and discounting the potential for interaction in
combined effects, we estimate that a maximum of 60% of cancer d
in the United States may be attributed to eight risk factors: tob
alcohol, ionizing and solar radiations, occupations, infectious ag
obesity, and physical inactivity.
97
Click here for quick links to
Annual Reviews content online,
including:
Other articles in this volume
Top cited articles
Top downloaded articles
Our comprehensive search
FurtherANNUAL
REVIEWS
7/27/2019 ARPH Schottenfeld Final
2/25
INTRODUCTIONIn 1981, Doll & Peto (27) coauthored a land-
mark publication that presented quantitative
estimates of avoidable risks of cancer in the
United States. The objective of their report
was to assess the evidence relating to ways of
avoiding or delaying the onset of cancers in
specific organ sites and to estimate the per-centage reductions in age-standardized cancer
mortality that would be achieved by removing
various lifestyle behavioral and environmental
risk factors that were prevalent in the popula-
tion. Estimates of the avoidability of specific
cancers were based on ranges of differences
in global cancer mortality rates in different
populations and geographic areas; differences
in risks for specific cancer sites between
migrants and indigenous populations that vary
by age at migration and duration of residence;
and epidemiologic studies of putative causes of
cancers and their impact on mortality rates and
trends. The referent low rates were derived
from international cancer incidence registry
data for 19681972 (142). On the basis of
these comparisons and of assumptions based
on minimum risk exposure distributions, Doll
& Peto concluded that, theoretically, 75% to
80% of cancer deaths in the United States in
the 1970s could have been avoided.
In the late 1970s and prior to the Doll &
Peto publication, the worlds population ex-
ceeded four billion, and there were an estimated
four million cancer deaths on average each year
(90). For the years 19751979, total US can-
cer mortality was the second leading cause of
death, accounting for 377,312 deaths, or 19.8%
of total deaths. Deaths due to cancers of the
breast, colon and rectum, and lung comprised
48% of cancer deaths in women, compared
with 56% of deaths in men due to cancers of
the prostate, colon and rectum, and lung (124).
In 2008, the worlds population was es-
timated to be 6.7 billion, and there were on
average, based on the GLOBOCAN 2008
statistics, 7.6 million cancer deaths and 12.7
million cancer cases (36). The report estimated
that 64% of the cancer deaths and 56% of the
cancer cases were registered in the econ
mically developing countries in Africa, As
and Latin America. The global projection f
the year 2020 is a population of 7.5 billio
in which there will be more than 10 millio
cancer deaths worldwide (68, 116).
In the United States, beginning with t
year 2000, cancer mortality surpassed heart dease as the underlying cause of death in wom
4079 years of age and in men 6079 years
age. The peak years for age-standardized ca
cer death rates were 1990 and 1991 in men an
women, respectively. However, the numb
of cancer deaths in all age groups persisted
the second leading cause of death, accountin
for 562,875 deaths in 2007, or 23.2% of tot
deaths. Cancer death rates, all sites combine
decreased by 1.9% per year in men and by 1.5
per year in women during 20022007. Redu
tions in overall cancer death rates since 199
resulted in 890,000 fewer cancer deaths th
expected by 2007. Lung, prostate, and colore
tal cancers comprised 80% of the decrease
cancer mortality in men. Breast and colorec
cancers accounted for 60% of the decrease
cancer mortality in women (63). However, rat
during 19992008 were increasing for seve
cancer sites, including human papillomaviru
related oropharyngeal squamous-cell canc
esophageal, pancreatic, liver and intrahepa
bile duct, thyroid, and renal cell adenoca
cinomas; and cutaneous melanoma. T
papillomavirus-related oropharyngeal cance
represented a subgroup that was HPV-
DNA-positive and comprised 2040%
oropharyngeal cancers reported in the Unit
States during the past 10 years (125). Of mo
than 1.5 million cancer cases diagnosed in t
United States each year, an estimated 16
(1 in 6) occur among cancer survivors of
or more years. In a 25-year study utilizi
the National Cancer Institutes Surveillan
Epidemiology and End Results (SEER) re
istry, the cumulative incidence of seco
primary cancers was 5.0%, 8.4%, 10.8%, an
13.7% at 5, 10, 15, and 25 years, respective
(61).
98 Schottenfeld et al.
7/27/2019 ARPH Schottenfeld Final
3/25
The objective of this review is to provide a
current perspective on the avoidable causes of
global and US cancer incidence and mortality.
Our approach will be based on a comprehensive
review of epidemiologic studies published since
the Doll & Peto report. Where appropriate,
we reference studies conducted in the United
States and in countries and populations outsideof the United States. Population-based cohort
and case-control studies and national surveys
of lifestyle behavioral risk factors will provide
the estimates for multivariable-adjusted relative
risks, distributions of prevalence proportions of
risk factors, and the precision of estimated pop-
ulation attributable fractions.
The population attributable fraction (PAF)
or excess fraction is used to quantify the
impact of a causal risk factor in a population:
the proportion of cases that would not have
occurred in the absence of exposure (110).
The measure was proposed in 1953 by Morton
Levin while describing the association between
cigarette smoking and lung cancer (76). As a
valid measure of the population burden of a
disease associated with a specific risk factor,
health professionals assume that the PAF is not
influenced by selection or misclassification bias,
nor confounded by the uncontrolled distribu-
tion of covariate causal factors (89). Thus the
formula for a single binary exposure variable is
PAF = Pe(RR 1)/Pe(RR 1) + 1,
where Pe is the proportion of the study
population exposed or estimated from
population-based controls and RR is the risk
ratio, rate ratio, or odds ratio. [An alternative
formula derives the attributable fraction among
the exposed cases (AFe) and multiplies AFe by
the proportion of total cases exposed.] When
the exposure is classified into more than two
categories, the formula is then modified to indi-catesummationoftheproductsoftheP(ith) ex-
posure levels and stratum-specific estimations
of relative risk. The summation of attributable
fractions for different environmental exposures
may not be appropriate when substantial over-
lap in the distribution of risk factors is assumed.
CANCER PATTERNS INDEVELOPING COUNTRIES
Of the total 59 million global deaths in 2008,
31% were attributed to cardiovascular diseases,
and 1213% to cancers in all sites (61, 62).
The global burden of cancer in low- and
middle-income countries (LMICs) is projected
to increase because of aging, increasing urban-ization, and expansion of the population at risk,
in conjunction with the prevalence trends of
major risk factors (138). When compared with
industrialized countries, LMICs in 2008 expe-
rienced a higher proportion of uterine cervical,
stomach, liver, oral cavity and pharyngeal,
esophageal, and HIV-associated cancers. Lung
and breast cancers are leading causes of mortal-
ity in both LMICs and industrialized countries.
The proportion of incident cancers diagnosed
in LMICs attributed to infectious agents wasestimated to vary from 20% to 30% (68, 95).
Future cancer trends in the LMICs will re-
flect global shifts in population distributions
of lifestyle and environmental exposures, such
as tobacco, and the cancer-causing infectious
agents, as well as exposures to occupational and
environmental carcinogenic agents (87). As-
sessment of global trends assumes an increas-
ing commitment to developing more complete
and accurate cancer surveillance registries that
are maintained by trained health professionalswith the collaboration and support of medical
and public health organizations. The sophisti-
cation of a committed public health infrastruc-
ture will enable the implementation of effective
interventions in primary lifestyle-based cancer
prevention and cancer-screening examinations.
MAJOR DETERMINANTSOF CANCER
Epidemiologic, biochemical, and moleculargenetic studies have provided a conceptual
foundation for multistep carcinogenesis.
Hanahan & Weinberg, in their review of the
hallmarks of cancer, described six biological
events in the interaction of cancer cells and the
immune mechanisms of the human host. These
www.annualreviews.org Risk Factors and Global Cancer Burden 99
7/27/2019 ARPH Schottenfeld Final
4/25
DNA methylation:attachment of methylgroups to DNAcytosine basesassociated withreduced or modulated
gene transcription
Histonemodification: histoneproteins make up thenucleosomes around
which DNA is coiledand upon whichepigenetic events maybe expressed
Tumor suppressorgenes: genesresponsible for
constraining cellneoplasticproliferation orfurthering celldifferentiation orphysiologic cell death
Proto-oncogenes:normal cellular genesthat, upon alterationby DNA-damagingagents, acquire theability to function asoncogenes, or genes
that transform cells
events include sustaining proliferative signal-
ing, evading the effects of intrinsic growth
suppressors, resisting apoptosis or the genetic
factors that regulate and program physiologic
cell death, enabling replicative immortality,
inducing angiogenesis, and activating mecha-
nisms that interfere with cell-cell adhesion and
cell-extracellular matrix attachment, resultingin local invasion and distant dissemination
of cancer cells (51). Experimental models of
chemical carcinogenesis have demonstrated
multistep phases of initiation, promotion,
neoplastic cell transformation or conversion,
and progression as a result of the accumulation
of adverse genetic and epigenetic events.
Chemical agents that are tumor promoters
facilitate clonal expansion of initiated cells.
Examples of agents with tumor-promoting
properties include tobacco smoke condensate,
ethanol, sex steroid hormones, bile acids,
dioxins, and agents that are chronic irritants or
evoke an inflammatory response.
Epigenetic events are composed of stable
and heritable, or potentially heritable, alter-
ations in gene expression that do not entail a
changein DNA sequence. Epigenetic eventsare
associated with patterns of DNA methylation
and histone modification that serve to modulate
the expression of tumor suppressor genes and
proto-oncogenes. Epigenetic mechanisms are
essential for normal function and development
of human cells and tissues, as well as for
maintenance of tissue-specific gene-expression
patterns. Epigenetic events are intimately asso-
ciated with fetal organdevelopment,pathologic
events associated with aging, biochemical ef-
fects of micronutrients, and the tumorigenic
effects of cytokine mediators of chronic
inflammation (39, 122).
TobaccoNo single measure is known that would have as
great an impact on the number of deaths at-
tributable to cancer as a reduction in the use of
tobacco.
Doll & Peto (27)
During the years 20002007, tobacco use h
been associated with 56 milliondeaths per ye
worldwide, with 15% of those deaths due
cancer (65). Globally, among men and wome
between the ages of 30 and 69 years, cigaret
smoking was associated with 31% of all ca
cer deaths in men and 6% in women. If curre
trends in the patterns of smoking continue, J(65) projects that tobacco-related cancer mo
tality will double by 2030, with 70% of deat
occurring in LMICs.
The International Agency for Research
Cancer (IARC) listed 72 compounds in tobac
smoke that were sufficient or probabl
causes of human cancers. The most importan
based on their carcinogenic potency and esta
lished levels in cigarette smoke, were polycyc
aromatic hydrocarbons, N-nitrosamines, ar
matic amines, 1,3-butadiene, benzene, a
various aldehydes (58).
Nineteen cancer sites are currently a
tributable to cigarette smoking (Table 1). T
associated relative risks are influenced by bo
behavioral and host characteristics. The k
determinants of relative risk in association wi
smoking-exposure patterns include avera
intensity and duration of dose, measur
in number of cigarettes smoked per da
duration of use, pack-years of exposure, age
initiation, depth and frequency of inhalatio
tar concentration, use of filters, and number
years since quitting (among former smoker
In the British Physicians Study, among tho
who stopped smoking at ages 30, 40, an
50 years, the cumulative risks of lung canc
mortality by age 75 years were 2%, 3%, an
6%, respectively, compared with the risi
cumulative risk of 16% in those who continu
to smoke (30). The modeling of the dynami
of declining relative risks after smoking ce
sation has indicated that the major factors a
prior duration and intensity of smoking, a
at initiation, and age at cessation. Similar r
ductions in relative risk have been described
studies conducted in the United States, wher
since 2002, the number of former smoke
(about 47 million) has exceeded that of curre
100 Schottenfeld et al.
7/27/2019 ARPH Schottenfeld Final
5/25
Table 1 Tobacco-related cancer sites
System Organ site
Respiratory Lung and bronchus (all cell types), larynx, nasal cavity, paranasal sinuses,
nasopharynx
Upper digestive Oral cavity, pharynx (oropharynx, hypopharynx), esophagus (squamous
cell and adenocarcinoma)
Gastrointestinal Stomach, liver, pancreas, large intestine
Renal and lower urinary tract Kidney (renal cell carcinoma), kidney pelvis, ureter, urinary bladder(transitional cell carcinoma)
Female reproductive Uterine cervix, ovary (mucinous carcinoma cell type increased and
endometrioid cell type decreased in current smokers)
Hematologic Myeloid leukemia
smokers (about 45 million or 19% of adults)
(131). Currently, more than 50% of annual
lung cancer incidence in the United States is
diagnosed in former smokers. Susceptibility to
the deleterious effects of carcinogens containedin tobacco smoke may be influenced by genetic
polymorphisms in DNA repair capacity genes
and by polymorphisms that regulate activa-
tion, detoxification, and clearance of tobacco
procarcinogenic metabolites.
The pervasive nature of tobacco use and its
impact on the global cancer burden underscore
the importance of surveillance and assessment
of smoking trends. Over the past 30 years,
cigarette tobacco consumption, adjusted for
population size, has decreased by50% in the
United States and the United Kingdom, while
increasing significantly in China, Indonesia,
India, the Russian Federation, and Eastern
European and Latin American countries (40,
66, 84). The gender disparity in smoking
prevalence is more prominent among LMICs
(male to female ratio 6:1) compared with
high-income countries (1.75:1) (66). Within
LMICs, the prevalence of tobacco use increases
with urbanization (94).
Danaei and colleagues (24) reported on the
estimates of PAFs for tobacco by tumor type
for both LMICs and high-income countries
using cancer mortality data gathered by the
World Health Organization (WHO) in 2001.
Tobacco use was estimated to account for
29% of all cancer mortality in high-income
countries and 18% in LMICs. The US surgeon
general estimated that 30% of all cancer deaths
in the United States, ranging from 30% to
35% in men and 20% to 25% in women, were
attributable to exposure to tobacco smoke, anestimate that was comparable to that of Doll
and Peto (40, 19). In a 2004 report, the IARC
concluded that exposure to secondhand smoke
[or environmental tobacco smoke (ETS)] was
causally related to lung cancer in nonsmokers
(58). Precise measurement of exposure to
ETS is difficult, with most population-based
investigations focused on the spouses, children,
or coworkers of smokers. The results of a
meta-analysis published by IARC concluded
that, compared with the spouses of nonsmok-
ers, the risk of lung cancer associated with
having a spouse who smokes was 24% higher in
women and 37% higher in men (58). The risk
of lung cancer among nonsmokers exposed to
secondhand smoke in the workplace was 12%
higher in men and 19% higher in women than
in unexposed workers (58). In 2011, Parkin
estimated that the attributable fraction for lung
cancer cases in the United Kingdom associated
with ETS in both the home and the workplace
was 1213% among nonsmoking men and
1516% among nonsmoking women (97). The
US National Research Council concluded that
20% of lung cancer incidence in nonsmoking
men and women may be attributable to ETS
exposure, accounting for 2% to 3% of all lung
cancer cases (92, 58).
www.annualreviews.org Risk Factors and Global Cancer Burden 101
7/27/2019 ARPH Schottenfeld Final
6/25
Alcohol
[. . .] we arrive at an attributable proportion of
about 3% of all cancer deaths in both sexes. The
range of uncertainty in this estimate is quite nar-
row and it is most implausible that the true per-
centage lies outside the range of 24%.
Doll & Peto (27)
In 1988, the IARC classified ethyl alcohol as a
Group 1 carcinogen and its primary metabolite,
acetaldehyde, as a possible human carcinogen
(Group 2 B). In 2009, an IARC working
group concluded that acetaldehyde was a
Group 1 human carcinogen and confirmed the
earlier Group 1 classification of consumption
of ethanol in alcoholic beverages. Chronic
alcohol consumption has been associated
independently with risks of cancers of the oral
cavity, oropharynx, and hypopharynx; larynx
(glottis and supraglottis); esophagus; liver;
colon and rectum; and female breast (4, 8, 103).
The consensus of epidemiologic studies in-
dicates that the causal relationship is the result
of cumulative exposures to ethanol from the
various types of beverages. Although a thresh-
old has not been established, increasing risks af-
ter consumption of alcohol are readily evident
with consumption levels in excess of 1530 g per
day (equivalent to 12 drinks of beer, wine, or
spirits). In the WHO Global Burden of Disease
Project, a total 389,000 cancer cases in 2002
were attributable to alcohol consumption, rep-
resenting 3.6% of total cancers, 5.2% in men
and 1.7% in women. The PAFs for alcohol var-
ied by site ranging from 30% of cancers of the
oral cavity and pharynx to just less than 5% of
female breast cancers (120, 32, 55). In a pooled
analysis based on an international consortium
of more than 10,000 head and neck cancer pa-
tients, the carcinogenic effect of alcohol con-
sumption of 3 or more drinks per day in never
smokers was measured as an odds ratio of 2.04
[95% CI (confidence interval) = 1.29,3.21].
Among the never users of tobacco, 7% of cases
(95% CI = 416%) were attributed to alcohol
(55). In the United States and most industrial-
izedcountries,thePAFfortheupperaerodiges-
tivetract cancers caused by combined exposur
to alcohol and tobacco has been estimated
range from 70% to 80% (147, 21). The poten
ating effect of alcohol may reside in its functio
as a chemical solvent (121). Heterozygous ca
riers of the variant aldehyde dehydrogenase a
lele, ALDH22, when compared with modera
alcohol drinkers with wild-typeALDH2 allelare at higher risk of squamous cell carcinom
of the esophagus and upper digestive tract, pr
sumably because of elevated salivary, blood, a
mucosal concentrations of acetaldehyde (16)
Ionizing Radiation
If we assume that each individual receives a whole-
body dose of about 100 millirem, the total annual
dose received by the whole population will amount
to about 22 million rem . . . this would imply the
production of about 5,500 cancer deaths a year, or
1.4% of the total. . . it may be assumed that at low
doses and low dose rates the effect is approximately
proportional to the dose.
Doll & Peto (27)
Epidemiologic studies of radium-dial painte
(112), uranium miners (80), Japanese atom
bomb survivors (105), nuclear plant worke
(139), nuclear facility accidents as in Chernob
(3), irradiated cancer patients (114), or patien
with ankylosing spondylitis (144), and of ch
dren and adults following in-utero exposur
to radiation (26) have provided evidence
carcinogenicity from exposures to ionizi
radiations. Many human types of cancer ha
been linked to acute whole-body or protract
exposures to sparsely ionizing (i.e., low line
energy transfer) X-rays and gamma rays, wi
notable exceptions of chronic lymphocy
leukemia, Hodgkin lymphoma, maligna
melanoma, uterine cervical cancer, testicul
cancer, and prostate cancer (57, 135).
The National Council on Radiation Pr
tection and Measurements (NCRP) report
that 50% of the total population exposure
ionizing radiation emanated from natural bac
ground sources (91). The NCRP estimat
that the annual average per capita effecti
102 Schottenfeld et al.
7/27/2019 ARPH Schottenfeld Final
7/25
exposure dose was 2.4 millisievert, or 0.24 rem.
The effective exposure dose in sievert or rem is
a quantity that assigns a weighting factor on the
basis of differences in sensitivity of tissues to
radiobiologic effects and allows for comparing
populations exposed to different types of radia-
tion. More than 25 radioactive elements occur
naturally in rocks and plants, including radon,radium, uranium, thorium, and potassium.
Other sources of environmental radiation
originate from the sun and outer space.
Radon-222 exposure, resulting from ra-
dioactive decay of uranium-238, occurs mainly
through contamination of indoor air released
from soil and building materials. The average
annual residential radon exposure level in the
United States has been measured as equiva-
lent to 1.6 millisievert, comprising about two-
thirds of the total estimated natural background
level in the general population. The risk of lung
cancer attributed to inhalation of radon gas is
due to the effects of short-lived alpha-emitting
decay products, principally polonium-218 and
polonium-214, that deposit on the epithelial
cells lining the bronchial airways (52).
In a meta-analysis based on 8 case-control
studies conducted in the United States,
Sweden, Finland, and China, the estimated
odds ratio for lung cancer for an exposure at
100 Bq/m3 (equivalent to 2.7 picocuries per
liter) was 1.09 (95% CI = 1.00 to 1.19) (79).
Pooling of 13 European case-control studies
reported a relative risk of 1.16 (95% CI = 1.05
to 1.31) for lung cancer in relation to a radon
exposure level of 100 Bq/m3. At this exposure
level, the cumulative risk of lung cancer in
nonsmokers by age 75 years was projected to be
0.47%, and in cigarette smokers, 12% (53, 88).
On the basis of studies in Europe and in
the United States, domestic radon exposures
have been estimated to cause 515% of total
annual lung cancer cases. The joint effect of
exposures to radon progeny and tobacco smoke
is most consistent with a submultiplicative
interaction. The National Research Council
estimated that 15,40021,000 lung cancer
deaths per year were attributed to domestic
radon exposure, of which 2,1002,900 lung
cancer deaths occurred in nonsmokers (93).
The US Environmental Protection Agency
(EPA) has set 4pCi/L as an action level for
domestic radon levels requiring remediation
(43). The EPA estimates that as many as
eight million homes in the United States have
elevated radon levels. Remediation can be
initiated by the homeowner using a variety ofmethods, including sealing cracks in floors and
walls, increasing ventilation, and using pipes
and fans in subslab depressurization (43).
The National Research Council and the
NCRP concluded that no more than 2% of all
cancer deaths in the United States may be at-
tributed to natural background radiation (93,
91). Doll & Peto published subsequently that
the proportion of cancer deaths in the United
Kingdom that may be attributed to all sources
of ionizing radiation was 45% (28, 29).
Currently, medical exposures to ionizing
radiation contribute to 48% of the total US
population radiation exposure. In contrast, in
the early 1980s, medical exposures accounted
for only 15% of all radiation exposures (11).
Over the past 30 years, the average radiation
dose from medical imaging has increased about
sixfold, from 0.5 millisievert to 3.0 millisievert
(35, 44). Included under this category are
the percentages of the population exposure
doses attributed to computed tomography
(CT) (24%); nuclear medicine, including
use of radiopharmaceuticals and radiotracers
(12%); interventional fluoroscopy (7%); and
conventional radiography and fluoroscopy
(5%). Consumer products and industrial and
occupational exposures accounted for 2% of
the total. CT and nuclear imaging are the ma-
jor sources of medical radiation exposure (2).
Since its introduction in 1972, the number of
CT procedures has increased proportionately
from 8% to 15% each year. In 2006, there were
67 million estimated CT procedures in the
United States, compared with 293 million con-
ventional radiography and fluoroscopy proce-
dures. The radiation dose to individual organs
from a CT procedure will depend on the num-
ber of scans, tube current and scanning time,
tube voltage, the degree of overlap between
www.annualreviews.org Risk Factors and Global Cancer Burden 103
7/27/2019 ARPH Schottenfeld Final
8/25
adjacent tissue slices, and body mass of the
patient. Depending on machine settings, the
effective exposure dose to an organ may range
from 1 to 15 millisievert per scan (67, 127).
Current estimates, based on theoretical models,
are that 0.4% of all cancers in the United States
may be attributable to the radiation from CT
examinations (10). The estimated number ofCT procedures performed in 2007 exceeded 70
million, and these cases were projected to result
in 29,000 (95% CI = 15,00045,000) future
cancers (6). With multiple scans per procedure,
a future estimate for medical exposures may be
in the range of 1.52.0% of all cancers.
Solar Radiation
At this stage we may, perhaps, attribute 90% of lip
cancers and 50% or more of melanomas, as well as
80% of other skin cancers, to UV light, in which
case sunlight. . . would account for between 1 and
2% of all cancer deaths.
Doll & Peto (27)
Epidemiologic studies have established that a
pattern of chronic cumulative, work-related
exposure to solar radiation is associated with
the risk of cutaneous squamous cell carcinoma
(SCC), in contrast to a pattern of intermittent,
recreational exposure that is more commonly
associated with cutaneous and ocular melanoma
and basal cell carcinoma (BCC) (111). BCCs
and SCCs are the most commonly diagnosed
cancers in the white population in the United
States. Special surveys conducted in the United
States have estimated theannual incidence to be
in excess of one million cases per year (1). In ad-
dition, population-based studieshave estimated
1,0002,000 deaths each year, accounting for
0.20.4% of total annual cancer deaths (64).
BCC is by far more common among the
keratinocytic carcinomas, comprising 7080%
in white males and 8090% in white females
(69).
Cutaneous malignant melanoma (CMM)
is the most lethal form of skin cancer. There
were 11,800 deaths due to melanoma in US
men and women in 2010, or 2% of total cancer
deaths. The rate of increase of CMM in th
United States was 6% per year in the deca
19701979 and 3% per year over the past tw
decades (134). Melanocytes, the cells of orig
of CMM, arise from neural crest progenit
cells that migrate to the skin during embryog
nesis, concentrating in the epidermal-derm
junction, uveal epithelium, and sinonasal, oranal, and rectal mucosa (60). The probabili
of malignant transformation of a melanocy
is the result of complex interactions of exp
sure patterns to ultraviolet (UV) radiatio
genetic susceptibility, and anatomic locati
(22, 47). The patterns of sun exposure
childhood and adolescence, and the severi
of acute sunburn injury, are important ri
events for subsequent precursor and invasi
keratinocytic and melanocytic neoplasms. T
profile for increased risk of melanoma includ
the number, distribution, and morphology
nevi, light skin color, poor tanning abili
light eye color, extent of freckling, red
blond hair, and a family history of melanom
Approximately 510% of melanoma patien
are from high-risk families (77). The intensi
of ultraviolet radiation (UVR) at the earth
surface is greater at latitudes closer to t
equator and at increasing altitudes. Absorptio
of UVR by stratospheric ozone attenuat
transmission of the UVR spectrum. As a co
sequence of the ozone shield, UVA and UV
comprise a much diminished portion of t
emitted solar radiations, but they are primar
responsible for the suns pathological effec
The UVR that reaches the earths surfa
consists of95% UVA and 5% UVB (29, 49
In a survey in France, the attributab
fraction for UVR and total cancer mortality
the year 2000 was 0.7% for men and wom
combined (9). This estimate may be compar
with the 2003 estimate by Doll & Peto, th
the proportion of cancer deaths in the Unit
Kingdom attributed to UVR was 1% (2
Parkin estimated an attributable fraction
3.5% for malignant melanoma incidence in t
United Kingdom in 2010 (96). Consistent wi
the original Doll & Peto report, we estima
12% in the United States for solar radiatio
104 Schottenfeld et al.
7/27/2019 ARPH Schottenfeld Final
9/25
and combined mortality for keratinocytic
neoplasms and melanoma.
Exposures to artificial sources of UV radi-
ation, such as sunlamps, sun beds, and halogen
lamps, have been linked with increased risks of
cutaneous and ocular melanomas and of actinic
keratoses and keratinocytic carcinomas (59).
In the 1980s, 1% of American adults reportedusing indoor tanning facilities. Currently,
tanning beds are used by 30 million Americans,
or 10% of the population (37, 119). In a
meta-analysis of case-control studies covering
more than 7,000 cases of CMM, published by
IARC, the summary relative risk of indoor tan-
ning was 1.15 (95% CI = 1.001.31). For the
subgroup in whom the first exposure occurred
before age 35 years, the summary relative risk
was 1.75 (95% CI = 1.352.26) (73).
Regular use of broad-spectrum sunscreens
is an effective adjunct in reducing risk of actinic
keratoses and SCC (7). In a community-based,
randomized controlled clinical trial conducted
in Queensland, Australia, the use of a broad-
spectrum SPF 15+ sunscreen resulted in a
40% reduction (95% CI = 0.460.81) in risk
of SCCs (136).
Occupational Exposures
Although different figures may, of course, apply
to other countries, the minimum proportion of all
current U.S. cancer deaths attributable to occu-
pation can be hardly less than 2 or 3%. Occupa-
tional cancer, moreover, tends to be concentrated
among relatively small groups of people among
whom the risk of developing the disease may be
quite large . . . .
Doll & Peto (27)
Dreyer et al. (31), in a study of populations
in Norway and Sweden, concluded that indus-
trial carcinogens accounted for 3% of all can-
cer cases in men and
7/27/2019 ARPH Schottenfeld Final
10/25
Table 2 Biologic agents and human cancersa
Agent Organ site(s)
Viruses
HPV Uterine cervix, oropharyngeal, anogenital
HBV/HCV Liver, non-Hodgkin lymphoma (HCV)
EBV Lymphoid tissues: non-Hodgkin lymphomas, including Burkitt,
AIDS-related, posttransplant lymphoproliferative disorders; Hodgkin
lymphoma;Epithelial tissues: nasopharyngeal carcinoma, gastric carcinoma (?)
HHV-8 Kaposi sarcoma, primary effusion lymphoma, Castlemans multicentric
lymphoproliferative disease
HTLV-1 T-cell leukemia, lymphoma
MCPyV Merkel cell carcinoma (neuroendocrine tumor of dermis)
Bacteria
Helicobacter pylori Stomach: carcinoma, B-cell MALT lymphoma (mucosa-associated
lymphoid tumor)
Parasites
Schistosoma haematobium Urinary bladder
Liver flukes Liver, bile duct, cholangiocarcinomaFungi
Aspergillus(aflatoxin) Liver
aAbbreviations: EBV, Epstein-Barr virus; HBV, hepatitis B virus; HCV, hepatitis C virus; HHV-8, human herpes virus 8
HPV, human papilloma virus; HTLV-1, human T lymphotropic virus type 1; MCPyV, Merkel cell polyoma virus.
Cytokines:
regulatory proteins ofthe immune systemthat are associated
with inflammatoryreactions, adaptiveimmune responses,and hematopoiesis
with H. pylori is associated with progression
of multifocal atrophic gastritis to intestinal
metaplasia, dysplasia, and adenocarcinoma,
located distal to the gastroesophageal junction,
in 0.1% to 3% of patients (121). The tumori-
genic effects of persistent infection by viral,
bacterial, and parasitic agents are mediated
through mechanisms of chronic inflammation
that sustain proliferative signaling and aberrant
adaptive immune responses. In the absence of a
prominent inflammatory response, integration
of segments of the microbial genome within
the host genome may be accompanied by
disruption of tumor-suppressing regulatory
mechanism expression. The pathophysiologic
significance of chronic inflammation in human
carcinogenesis is reviewed below in the context
of chronic infections with HBV and HCV and
hepatocellular carcinoma (HCC) (117).
HCC is the third most common cause of
global cancer mortality. Approximately 85% of
the cases are diagnosed in developing countries
in Southeast Asia and sub-Saharan Africa whe
HBV is endemic. Both HBV (more than 50
of HCC cases) and HCV (30%) are maj
causes of the estimated 700,000 annual cas
worldwide (33).
The cumulative lifetime risk of HCC
patients chronically infected with HBV is es
mated to be 1025%. The latency period fro
onset of infection to diagnosis of liver canc
ranges from 20 to 50 years. The level of risk
correlated with HBV viral load and patholog
indicators of cirrhosis and amplified by coinfe
tion with HCV, HIV, and Delta hepatitis viru
as well as exposures to ethanol, aflatoxin, t
bacco, and obesity. The HBV DNA integrat
randomly into the host cell genome. Cytotox
T-lymphocytes and cytokines interact wi
infected hepatocytes and are accompanied
recurring cycles of cellular injury, necros
and regeneration. In contrast to HBV, HCV
not integrated into the host genome. Chron
HCV infection affects 2.73.9 million perso
106 Schottenfeld et al.
7/27/2019 ARPH Schottenfeld Final
11/25
in the United States and is associated with liver
fibrosis, cirrhosis, and liver cancer. The annual
incidence of HCC in HCV-infected patients
with cirrhosis is 38%. Biomarkers of chronic
HCV infection are detected in 8090% of
HCC patients in Japan and in 3050% of
patients in the United States (33, 81).
By 2007, the Joint United Nations Programon HIV/AIDS (UNAIDS) estimated the global
prevalence of HIV-1 infection to be 33.2 mil-
lion. HIV prevalence proportions ranged from
less than 0.5% in most developed countries to
an upper limit of 2530% in Central and South-
ern Africa. The estimates reflected assumptions
about the stability of survival rates and mi-
gration patterns (12, 141). In 2007, UNAIDS
assumed that the median survival in the infected
population increased from 9 years to 11 years,
which resulted in a reduction in the estimated
global incidence from 4.1 million in 2006 to
2.5 million in 2007. UNAIDS estimated that
2.5 million deaths in LMICs were averted since
1995 since the introduction of antiretroviral
therapy. Refinements in future estimates will
depend on the enhanced specificity and avail-
ability of immunoassays for diagnosing new
infections.
Before the introduction of highly active
antiretroviral therapy (HAART), a number of
cancers were identified as AIDS-defining can-
cers (ADCs). These included Kaposi sarcoma;
non-Hodgkin lymphoma, most commonly
of B-cell phenotype, that included entities
classified as primary central nervous system
lymphoma, large-cell immunoblastic lym-
phoma, and Burkitt lymphoma; and cancer of
the uterine cervix. During the period following
the introduction of HAART, the relative risks
of ADCs changed substantially. In addition,
cancers that were not designated as ADCs were
reported in patients with HIV. The non-ADCs
included Hodgkin lymphoma, anogenital can-
cers, keratinocytic (nonmelanoma) skin cancer,
SCC of the conjunctiva, and HCC (15, 50,
104). HIV infection is indirectly carcinogenic
as a result of severe lymphocyte depletion
and impaired immune function. The pattern
of neoplastic sequellae results from increased
expression of oncogenic viruses, namely
Kaposi sarcoma herpes virus, Epstein-Barr
virus, human papillomaviruses, hepatitis B
and C viruses, and/or interactions with envi-
ronmental agents such as UV radiation and
tobacco.
Obesity: Energy Consumptionand Expenditure
[T]he role of overnutrition should perhaps come
first rather than a list of aspects of diet which may
affect the incidence of cancer, even though the rel-
evant mechanisms remain obscure.
Doll & Peto (27)
The World Health Organization (WHO) es-
timated in 2006 that throughout the world,
1.6 billion persons aged 15 years and older were
overweight, among whom 400 million were
obese (148). Currently the US National Insti-
tutes of Health (NIH), Dietary Guidelines for
Americans, and the WHO use the body mass
index (BMI), calculated from the ratio of the
weight in kilograms (kg) divided by the height
in meters squared (m2), as a criterion for defin-
ing overweight and obesity (71). For the US
adult population, an acceptable BMI is in the
range of 18.524.9 kg/m2, overweight is clas-
sified as ranging from 25.029.9 kg/m2, and
obese is classified as 30.0 kg/m2. The obe-
sity category has been further subclassified as
follows: Class 1 = 30.034.9 kg/m2, Class 2 =
35.039.9 kg/m2, and Class 3 = 40 kg/m2.
BMI is correlated with percentage of body fat,
but it does not provide information concerning
regional differences in visceral intra-abdominal
and subcutaneous fat distribution. The degree
of adiposity associated with a given level of BMI
may vary by age, gender, and racial or ethnic
group. In studies of health outcomes in rela-
tionship to adiposity in elderly menand women,
concurrent assessment of BMI may not be an
appropriate measure because of changes in body
mass and composition that occur commonly
with aging (128).
On the basis of the National Health and Nu-
trition ExaminationSurvey (NHANES) among
www.annualreviews.org Risk Factors and Global Cancer Burden 107
7/27/2019 ARPH Schottenfeld Final
12/25
US adults in 19992008, the age-adjusted
prevalence of obesity was 33.8% overall, 32.2%
among men, and 35.5% among women. The
estimated prevalence of the surveyed popula-
tion who were overweight and obese combined
was 72.3% for men and 64.1% for women (38).
Between 1980 and 2004, the prevalence of obe-
sity doubledin adults, whereas theprevalence ofoverweight tripled in children and adolescents
aged 619 years (78). Obese adolescents are
at substantially higher risk of protracted obe-
sity accompanied by adverse health outcomes
as young adults (130).
Beyond the assessment of total adiposity is
the consideration of regional distribution of
fat. Measurements of the waist circumference,
where the measuring tape is placed at the
level of the iliac crest and measured at the
end of normal expiration, or measurement
of the waist-to-hip ratio (WHR) or waist-to-
thigh ratio (WTR), are positively correlated
with intra-abdominal, visceral fat deposition.
However, the anthropometric ratios do not
reflect only visceral fat accumulation. In each
instance, the numerator provides an estimate
of total and abdominal fat mass, and the
denominator reflects overall body tissue mass,
including muscle mass and peripheral fat mass.
Thus, an increased WHR, namely 0.95 in
men and 0.80 in women, may reflect an
increase in visceral fat, decreased peripheral
subcutaneous fat or muscle, or both. Excessive,
intra-abdominal fat deposition, classified as
a waist circumference 102 cm in men and
88 cm in women, is associated with elevated
risks of coronary heart disease, hypertension,
ischemic stroke, type-2 diabetes, and a wide
spectrum of cancers of gastrointestinal, genital,
reproductive, kidney, hematopoietic, and
endocrine organ sites (100, 106, 150).
In the WHO technical report (148) on pre-
venting and managing the global epidemic of
obesity, the committee emphasized the com-
plexity of diverse societal, cultural, economic,
political, physical, and structural obesogenic
factors that influence food preferences, en-
ergy intake, and energy expenditure, as well as
potential interaction with genetic mechanisms
that influence individual susceptibility. Her
tability of common obesity, or the degree
which a quantitative trait is genetically dete
mined, expressed as the ratio of the additive g
netic variance to the total phenotypic varianc
has been estimated to range from 50% to 80%
The genetic contribution to the variability
the prevalence of obesity has been based oanalyses of family, twin, and adopted offsprin
studies (5). The putative effects of candida
genes may serve to regulate brain sensing of f
stores; energy homeostasis and rate of ener
expenditure; appetite, satiety, and the functio
ing of taste receptors; lipoprotein metabolism
and the activity of signaling peptides releas
from the gastrointestinal tract and adipo
tissue (18, 23, 34, 56, 102).
Adipocytes and fat-storage depots represe
a complex endocrine and metabolic syste
that plays an essential role in energy intak
energy expenditure, and lipid and carbohydra
metabolism. The pathogenesis of obesity
associated with a high influx of fatty acids fro
visceral fat into the portal circulation, insul
resistance, abnormal lipoprotein synthes
low-grade chronic inflammation, and aberra
production of adipokines and proinflammato
cytokines (137). The biochemistry of dysfun
tional fat tissue may impact human cancer ris
and cancer progression as a result of (a) insulresistance, hyperinsulinemia, and transie
increases in hepatic secretion of insulin-li
growth factor (IGF-1) and decreases in he
atic production of IGF-binding protein
(b) increased production and bioavailabiliof sex-steroid hormones due to increas
aromatization of adrenal-derived androge
and decreased production of sex hormon
binding globulins; (c) increased production proinflammatory cytokines, including tum
necrosis factor , interleukin-6 (IL-6), a
C-reactive protein; and (d) propensity for t
metabolic syndrome, associated with elevat
triglycerides and free fatty acids, insulin res
tance, and glucose intolerance/type-2 diabet
(25, 48, 70, 109, 140).
In a systematic review and synthesis
prospective studies conducted in Nor
108 Schottenfeld et al.
7/27/2019 ARPH Schottenfeld Final
13/25
America, Europe, Australia, and the Asia-
Pacific populations, Renehan et al. (108)
estimated relative risks of incident cancers in
15 organ sites in association with baseline in-
cremental BMI levels, standardized to 5 kg/m2.
In a subsequent publication, on the basis of a
survey of 30 European countries, investigators
concluded that 3.2% of all incident cancers inmen and 8.6% in women may be attributable
to excess body weight. The overall impact
amounted to more than 124,000 avoidable
cancer cases per year. Cancers of the breast,
endometrium, colon, and rectum accounted
for two-thirds of the attributable cases (107).
The relative risks of total cancer and site-
specific cancer mortality attributable to being
overweight or obese at baseline were reported
in a cohort of more than 900,000 adult men and
women participating in the American Cancer
Societys Cancer Prevention Study II. The pro-
portion of all cancer deaths, based on relative
risks derived for the entire cohort, attributable
to being overweight or obese at enrollment,
was 4.2% in men and 14.3% in women. In-
vestigators identified a subgroup of the cohort
that consisted of 383,594 participants who were
neversmokers.Theproportionofcancerdeaths
attributable to being overweight or obese at en-
rollment of US adults 50 years of age and older,
who never smoked, was estimated at 14.2% in
men and 19.8% in women. The PAFs, assumed
to be generalizable to the US population, were
derived on the basis of the relative risks esti-
mated in the cohort study, which were then
applied to the 19992000 NHANES of excess
body weight prevalence in men and women,
5069 years of age (14). The PAFs estimated
for excess body weight and individual cancer
sites in US adults in the year 2000 included
colorectal cancer in men (35.4%) and women
(20.8%), postmenopausal women with breast
cancer (22.6%), and endometrial (56.8%), renal
cell (42.5%), esophageal (52.4%), gastric cardia
(35.5%), and gallbladder (35.5%) carcinomas
(13).
Based on SEER (2007) incidence data,
NHANES (20052006) obesity prevalence
data, and a summary review of published
meta-analyses of cohort studies, Polednak (101)
estimated that 4% of total incident cancers
in men and 7% in women were attributed to
obesity. The overall estimate was 6%, with the
largest number of cancers in women being en-
dometrium and breast, and colorectal cancer in
men.
Since the mid-1980s, the avoidable role ofphysical inactivity in cancer mortality, indepen-
dent of, or interactive with, obesity and other
lifestyle risk factors, has been examined in ob-
servational epidemiologic studies (132). More
than 60 cohort and case-control studies con-
ducted worldwide have shown 2030% lower
risks of colon cancer in relation to increasing
hours per week and intensity levels (metabolic
equivalents or MET-hours per week) of phys-
ical activity (54). (One MET equals the rest-
ing metabolic rate and is roughly equivalent to
1 kilocalorie or 4.184 kilojoules per kilogram of
body weight.) In a review of 19 cohort studies,
Samad et al. (115) reported on the reduction
in relative risks for colon cancer in physically
active men (0.78; 95% CI = 0.680.91) and
women (0.71; 95% CI = 0.570.88). However,
the independent inverse association with level
of physical activity observed for colon cancer
hasnot been demonstrated for rectal cancer(41,
72, 74, 75, 133, 146).
In a cohort study of more than 47,000 male
health professionals, the multivariable-adjusted
relative risk of colon cancer in the most active
quintile, compared with the lowest, was 0.53
(95% CI = 0.320.88) (46). In the Nurses
Health Study, the relative risk of colon cancer
in the most active group was 0.54 (95% CI =
0.330.90) (83). Women who engaged in physi-
cal activityat a level of 21 MET-hours per week
for 40 years experienced a 49% reduction (95%
CI = 0.320.77) in risk of colon cancer, com-
pared with women who reported 2 MET-hours
of physical activity per week (143). In a system-
atic review of 50 studies, both cohort and case-
control, conducted in North America, Europe,
Asia, Australia, and New Zealand, the median
relative risk, comparing the most active partici-
pants with the least active, was 0.7 for men and
0.6 for women (74).
www.annualreviews.org Risk Factors and Global Cancer Burden 109
7/27/2019 ARPH Schottenfeld Final
14/25
The cancer-preventive biological mecha-
nisms that have been proposed for increased
physical activity in colorectal carcinogenesis in-
clude actions that (a) ameliorate the metaboliceffects of adiposity, notably insulin resistance;
(b) decrease levels of proinflammatory cy-tokines (e.g., the interleukins IL-1 and IL-6,
C-reactive protein, tumor necrosis factor
)and the adverse effects of a systemic inflamma-
tory response; (c) accelerate bowel transit time;
and(d) decrease fecal bile acid levels (17, 45, 82,86, 145).
A population-based case-control study
conducted in Northern California, Utah, and
Minnesota observed that 2025% of the adult
population was physically inactive and that
long-term high levels of vigorous activity were
associated with a reduced risk of colon cancer
(OR = 0.68; 95% CI = 0.520.87). The pop-
ulation attributable risk of colon cancer due to
lack of physical activity was estimated at 13%,
and 4.3 cases per 100,000 population were
preventable each year as a result of vigorous,
leisure-time physical activity (126). Frieden-
reich et al. (42) derived PAFs for a sedentary
lifestyle and colon cancer incidence for 15
European Union member countries reporting
slightly lower estimates in women ranging
from 6% to 11%, and in men, from 6% to 10%.
Numerous publications have shown, when
comparing the most active with the least ac-
tive women, an average reduction of 2040% in
relative risk of breast cancer in premenopausal
and postmenopausal women. Most studies have
shown decreasing risks in relationship to in-
creasing duration and intensity of activity (74).
Activity that is sustained throughout adult life,
or performed after menopause, is probably ben-
eficial in reducing breast cancer risk (85).
In the IARC Working Group Report (149)
on the avoidable causes of cancer mortality in
France in the year 2000, physical inactivity was
associated with a 32% increase (95% CI =
1.061.64) in risk of breast cancer. The preva-
lence of physical inactivity in adult women 18
65 years of age was 34%. The PAF for physical
inactivity and breast cancer may be estimated at
8.6% (95% CI = 5.0%11.6%).
ALLEVIATING THE BURDENOF CANCER IN THE UNITEDSTATES AND OTHER WESTERNCOUNTRIES
In their 1981 publication, Doll & Peto co
cluded that 7580% of cancer deaths in th
United States could have been avoided. T
overall estimates reflected uncertainties abo
diet (PAF = 35%, range: 1070%), but wit
out estimating attributable fractions for ob
sity or physical inactivity, and uncertainty abo
attributable risks for various infectious agen
(27). Doll & Peto defined diet as all mat
rials that occur in natural foods, are produc
during processes of storage, cooking, and dige
tion, or added as preservatives, or giving foo
color, flavor or consistency (p. 1226). Our cu
rent perspective for industrialized countries
summarized for the United Kingdom, Franc
and the United States (Table 3). The data sho
contrasting estimates for the three countries.
the review by Parkin, 14 lifestyle and enviro
mental risk factors were responsible for 43
of cancer cases (45% in men, 40% in wome
and for 50% of cancer deaths in 2010.
addition to the risk factors reviewed in det
above, Parkin assessed four dietary factors
low consumption of fruits and vegetables [PA
(combined men and women) = 4.7%], r
and processed meat consumption, low dieta
fiber, and saltand oral contraceptives, ho
mone replacement therapy, and reproducti
factors.
In their review of biologic agents, lifesty
behavioral patterns, and physical environme
tal factors that are established determinants
cancer incidence and mortality, Colditz & W
(20) concluded that 5060% of cancer deat
and more than 60% of cancer cases in th
United States were potentially avoidable. Sim
ilarly in our analysis we suggest that 60%
cancer deaths in the United States may be a
tributable to eight risk factors. Because we m
assume some degree of overlap in the distr
bution of such combinations of risk factors
tobacco and alcohol, and obesity and physic
inactivity, our estimate of 60% may represe
110 Schottenfeld et al.
7/27/2019 ARPH Schottenfeld Final
15/25
Table 3 Attributable fractions for selected causes of cancer mortality in the United States and France, and cancer inc
in the United Kingdom
Risk factor
Doll & Peto,
United States,
1970s (27)
WHO, France,
2000 (149)
Parkin, United
Kingdom, 2010
(96)
Schottenfeld et al., U
States, 200020
Tobacco
Men
Women
30% (range
2040%)
24%
33%
6%
19%
23%
16%
30%
3035%
2025%Alcohol
Men
Women
3% (range 24%) 7%
9%
3%
4%
45%
3%
34%
46%
12%
Ionizing radiation 12%a 2% 23%
Solar radiation 12%a 0.7% 3.5%b 12%
Occupation
Men
Women
4% (range
2%8%)
34%
7/27/2019 ARPH Schottenfeld Final
16/25
SUMMARY POINTS
1. Cancer incidence in low- and middle-income countries (LMICs) is projected to rise be-
cause of aging and expansion of the at-risk population, increasing urbanization, and the
persistence of exposures to HIV-related cancers, other cancer-causing biologic agents,
various forms of tobacco, and various sources of occupational and environmental car-
cinogenic agents.
2. LMICs experience higher proportions of uterine cervical, oropharyngeal, esophageal,
stomach, and liver cancers than do the industrialized countries. Lung and breast cancer
are leading global causes of cancer mortality.
3. The epidemiology and pathogenesis of eight lifestyle risk factors are estimated to be
determinants of60%of cancer mortality in theUnited States.These risk factors include
tobacco, alcohol, ionizing and solar radiations, occupations, biologic agents, obesity, and
physical inactivity.
DISCLOSURE STATEMENT
The authors are not aware of any affiliations, memberships, funding, or financial holdings thmight be perceived as affecting the objectivity of this review.
LITERATURE CITED
1. Albert MR, Weinstock MA. 2003. Keratinocyte carcinoma. CA Cancer J. Clin. 53:292302
2. Amis ES Jr, Butler PF, Applegate KE, Birnbaum SB, Brateman LF, et al. 2007. American College
Radiology white paper on radiation dose in medicine. J. Am. Coll. Radiol. 4:27284
3. Astakhova LN, Anspaugh LR, Beebe GW, Bouville A, Drozdovitch VV, et al. 1998. Chernobyl-relat
thyroid cancer in children of Belarus: a case-control study. Radiat. Res. 150:34956
4. Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, et al. 2007. Carcinogenicity of alcoholic beverag
Lancet Oncol. 8:29293
5. Bealess PL, Farooqi IS, ORahilly S. 2009. Genetics of Obesity Syndromes. Oxford: Oxford Univ. Press6. de Berrington GA, Mahesh M, Kim KP, Bhargavan M, Lewis R, et al. 2009. Projected cancer risks fro
computed tomographic scans performed in the United States in 2007. Arch. Intern. Med. 169:20717
7. Berwick M. 2007. Counterpoint: Sunscreen use is a safe and effective approach to skin cancer preventio
Cancer Epidemiol. Biomark. Prev. 16:192324
8. Boffetta P, Hashibe M. 2006. Alcohol and cancer. Lancet Oncol. 7:14956
9. Boffetta P, Tubiana M, Hill C, Boniol M, Aurengo A, et al. 2009. The causes of cancer in Fran
Ann. Oncol. 20:55055
10. Brenner DJ,Hall EJ. 2007. Computed tomographyan increasing source of radiation exposure.N. En
J. Med. 357:227784
11. Brenner DJ, Hricak H. 2010. Radiation exposure from medical imaging: time to regulate? JAM
304:2089
12. Brookmeyer R. 2010. Measuring the HIV/AIDS epidemic: approaches and challenges. Epidemiol. R32:2637
13. Calle EE, Kaaks R. 2004. Overweight, obesity and cancer: epidemiological evidence and proposed mec
anisms. Nat. Rev. Cancer4:57991
14. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. 2003. Overweight, obesity, and mortalityfro
cancer in a prospectively studied cohort of U.S. adults. N. Engl. J. Med. 348:162538
15. Casper C. 2011. The increasing burden of HIV-associated malignancies in resource-limited region
Annu. Rev. Med. 62:15770
112 Schottenfeld et al.
7/27/2019 ARPH Schottenfeld Final
17/25
16. Chen YJ, Chen C, Wu DC, Lee CH, Wu CI, et al. 2006. Interactive effects of lifetime alcohol consump-
tion and alcohol and aldehyde dehydrogenase polymorphisms on esophageal cancer risks. Int. J. Cancer
119:282731
17. Cho ER, Shin A, Kim J, Jee SH, Sung J. 2009. Leisure-time physical activity is associated with a reduced
risk for metabolic syndrome. Ann. Epidemiol. 19:78492
18. Clement K. 2005. Genetics of human obesity. J. Annu. Diabetol. Hotel Dieu 2005:3953
19. Cokkinides V, Bandi P, McMahon C, Jemal A, Glynn T, Ward E. 2009. Tobacco control in the United
Statesrecent progress and opportunities. CA Cancer J. Clin. 59:35265
20. Colditz GA, Wei EK. 2012. Preventability of cancer: the relative contributions of biologic, and socialand physical environmental determinants of cancer mortality. Annu. Rev. Public Health 33:13756
21. Corrao G, Bagnardi V, Zambon A, La Vecchia C. 2004. A meta-analysis of alcohol consumption and
the risk of 15 diseases. Prev. Med. 38:61319
22. Cress RD, Holly EA, Ahn DK, LeBoit PE, Sagebiel RW. 1995. Cutaneous melanoma in women:
anatomic distribution in relation to sun exposure and phenotype. Cancer Epidemiol. Biomark. Prev. 4:831
36
23. Cummings DE, Schwartz MW. 2003. Genetics and pathophysiology of human obesity. Annu. Rev. Med.
54:45371
24. DanaeiG, Vander HS,Lopez AD,MurrayCJ, Ezzati M. 2005. Causes of cancer in theworld:comparative
risk assessment of nine behavioural and environmental risk factors. Lancet366:178493
25. Day CP. 2006. From fat to inflammation. Gastroenterology 130:20710
26. Delongchamp RR, Mabuchi K, Yoshimoto Y, Preston DL. 1997. Cancer mortality among atomic bombsurvivors exposed in utero or as young children, October 1950May 1992. Radiat. Res. 147:38595
27. Doll R, Peto R. 1981. The causes of cancer: quantitative estimates of avoidable risks of cancer in the
United States today. J. Natl. Cancer Inst. 66:1191308
28. Doll R, Peto R. 1996. Epidemiology of cancer. In Oxford Textbook of Medicine, ed. DJ Weatherall,
JG Ledingham, DA Warrell, pp. 197222. New York: Oxford Univ. Press
29. Doll R, Peto R. 2003. Epidemiology of cancer. In Oxford Textbook of Medicine, ed. DA Warrell, TA Cox,
JD Firth, EJ Benz, pp. 195218. New York: Oxford Univ. Press
30. Doll R, Peto R, Boreham J, Sutherland I. 2004. Mortality in relation to smoking: 50 years observations
on male British doctors. Br. Med. J. 328:1519
31. Dreyer L, Andersen A, Pukkala E. 1997. Avoidable cancers in the Nordic countries. Occupation.APMIS
Suppl. 76:6879
32. Druesne-Pecollo N, Tehard B, Mallet Y, Gerber M, Norat T, et al. 2009. Alcohol and genetic polymor-phisms: effect on risk of alcohol-related cancer. Lancet Oncol. 10:17380
33. El-Serag HB. 2011. Hepatocellular carcinoma. N. Engl. J. Med. 365:111827
34. Farooqi IS, ORahilly S. 2005. Monogenic obesity in humans. Annu. Rev. Med. 56:44358
35. Fazel R, Krumholz HM, Wang Y, Ross JS, Chen J, et al. 2009. Exposure to low-dose ionizing radiation
from medical imaging procedures. N. Engl. J. Med. 361:84957
36. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. GLOBOCAN 2008: Cancer Incidence and
Mortality Worldwide. IARC CancerBase. No. 10. Lyon, Fr.: IARC
37. Fisher DE, James WD. 2010. Indoor tanningscience, behavior, and policy. N. Engl. J. Med. 363:9013
38. Flegal KM, Carroll MD, Ogden CL, Curtin LR. 2010. Prevalence and trends in obesity among US
adults, 19992008. JAMA 303:23541
39. Foley DL, Craig JM, Morley R, Olsson CA, Dwyer T, et al.2009. Prospects for epigenetic epidemiology.
Am. J. Epidemiol. 169:38940040. Forey B, Hamling J, Lee P, Wald N. 2009. International Smoking Statistics: A Collection of Historical Data
from 30 Economically Developed Countries. New York: Oxford Univ. Press
41. Friedenreich C, Norat T, Steindorf K, Boutron-Ruault MC, Pischon T, et al. 2006. Physical activity
and risk of colon and rectal cancers: the European prospective investigation into cancer and nutrition.
Cancer Epidemiol. Biomark. Prev. 15:2398407
42. Friedenreich CM, Neilson HK, Lynch BM. 2010. State of the epidemiological evidence on physical
activity and cancer prevention. Eur. J. Cancer46:2593604
www.annualreviews.org Risk Factors and Global Cancer Burden 113
7/27/2019 ARPH Schottenfeld Final
18/25
43. Frumkin H, Samet JM. 2001. Radon. CA Cancer J. Clin. 51:322, 33744
44. Furlow B. 2010. Radiation dose in computed tomography. Radiol. Technol. 81:43750
45. Giovannucci E. 2007. Metabolic syndrome, hyperinsulinemia, and colon cancer: a review. Am. J. Cl
Nutr. 86:s83642
46. Giovannucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. 1995. Physical activi
obesity, and risk for colon cancer and adenoma in men. Ann. Intern. Med. 122:32734
47. Green A. 1992. A theory of site distribution of melanomas: Queensland, Australia. Cancer Causes Contr
3:51316
48. Greenberg AS, Obin MS. 2006. Obesity and the role of adipose tissue in inflammation and metabolisAm. J. Clin. Nutr. 83:S46165
49. Gruber SB, Armstrong BK. 2006. Cutaneous and ocular melanoma. See Ref. 118, pp. 1196229
50. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. 2007. Incidence of cancers in people w
HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis. Lancet370:59
51. Hanahan D, Weinberg RA. 2011. Hallmarks of cancer: the next generation. Cell144:64674
52. Harley NH. 2008. Health effects of radiation and radioactive materials. In Casarett and Doulls Toxicolo
ed. CD Klassen, pp. 105382. New York: McGraw-Hill
53. Harley NH. 2009. Radon and lung cancer. In Environmental Toxicants, Human Exposures and Hea
Effects, ed. M Lippmann, pp. 1089120. Hoboken, NJ: Wiley
54. Harriss DJ, Atkinson G, Batterham A, George K, Cable NT, et al. 2009. Lifestyle factors and colorec
cancer risk (2): a systematic review and meta-analysis of associations with leisure-time physical activi
Colorectal Dis. 11:68970155. Hashibe M, Brennan P, Benhamou S, Castellsague X, Chen C, et al. 2007. Alcohol drinking in nev
users of tobacco, cigarette smoking in never drinkers, and the risk of head and neck cancer: pool
analysis in the International Head and Neck Cancer Epidemiology Consortium. J. Natl. Cancer In
99:77789
56. Hu HB. 2008. Genetic predictors of obesity. In Obesity Epidemiology, ed. HB Hu, pp. 43760. Oxfor
Oxford Univ. Press
57. IARC Monogr. Evaluation of Carcinog. Risks Hum. 2000. Ionizing Radiation, Part 1: X-Ray, Gamm
Radiation, and Neutrons, IARC Monogr. 75. Lyon, Fr.: IARC
58. IARC Monogr. Evaluation of Carcinog. Risks Hum. 2004. Tobacco Smoke and Involuntary Smoking. IAR
Monogr. 83. Lyon, Fr.: IARC
59. IARC Work. Group. 2006. The association of use of sunbeds with cutaneous melanoma and other sk
cancers: a systematic review. Int. J. Cancer120:111622
60. Ibrahim N, Haluska FG. 2009. Molecular pathogenesis of cutaneous melanocytic neoplasms. Annu. R
Pathol. Mech. Dis. 4:55179
61. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. 2011. Global cancer statistics. CA Cancer
Clin. 61:6990
62. Jemal A, Center MM, DeSantis C, Ward EM. 2010. Global patterns of cancer incidence and mortal
rates and trends. Cancer Epidemiol. Biomark. Prev. 19:1893907
63. Jemal A, Siegel R, Ward E, Murray T, Xu J, et al. 2006. Cancer statistics, 2006. CA Cancer J. Cl
56:10630
64. Jemal A, Siegel R, Xu J, Ward E. 2010. Cancer statistics, 2010. CA Cancer J. Clin. 60:277300
65. Jha P. 2009. Avoidable global cancer deaths and total deaths from smoking. Nat. Rev. Cancer9:6556
66. Jha P, Ranson MK, Nguyen SN, Yach D. 2002. Estimates of global and regional smoking prevalence
1995, by age and sex. Am. J. Public Health 92:10026
67. Johnson DA, Helft PR, Rex DK. 2009. CT and radiation-related cancer risktime for a paradigm shiNat. Rev. Gastroenterol. Hepatol. 6:73840
68. Kanavos P. 2006. The rising burden of cancer in the developing world.Ann. Oncol. 17(Suppl. 8):viii15
69. Karagas MR, Weinstock M, Nelson HH. 2006. Keratinocyte carcinomas (basal cell and squamous c
carcinomas of the skin). See Ref. 118, pp. 123050
70. Kershaw EE, Flier JS. 2004. Adipose tissue as an endocrine organ. J. Clin. Endocrinol. Metab. 89:2548
71. Kuczmarski RJ, Flegal KM. 2000. Criteria for definition of overweight in transition: background a
recommendations for the United States. Am. J. Clin. Nutr. 72:107481
114 Schottenfeld et al.
7/27/2019 ARPH Schottenfeld Final
19/25
72. Larsson SC, Rutegard J, Bergkvist L, Wolk A. 2006. Physical activity, obesity, and risk of colon and
rectal cancer in a cohort of Swedish men. Eur. J. Cancer42:259097
73. Lazovich D, Vogel RI, Berwick M, Weinstock MA, Anderson KE, Warshaw EM. 2010. Indoor tanning
and risk of melanoma: a case-control study in a highly exposed population. Cancer Epidemiol. Biomark.
Prev. 19:155768
74. Lee I-M, Oguma Y. 2006. Physical activity. See Ref. 118, pp. 44967
75. Lee IM, Paffenbarger RS Jr, Hsieh C. 1991. Physical activity and risk of developing colorectal cancer
among college alumni. J. Natl. Cancer Inst. 83:132429
76. Levin ML. 1953. The occurrence of lung cancer in man. Acta Union Int. Contra Cancrum 9:5314177. Lindor NM, McMaster ML, Lindor CJ, Greene MH. 2008. Concise handbook of familial cancer sus-
ceptibility. 2nd ed. J. Natl. Cancer Inst. Monogr. 2008(38):193
78. Lobstein T. 2000. Prevalence and trends in childhood obesity. In Obesity Epidemiology: From Etiology to
Public Health, ed. D Crawford, RW Jeffrey, K Ball, J Brug, pp. 316. New York: Oxford Univ. Press
79. Lubin JH, Boice JD Jr. 1997. Lung cancer risk from residential radon: meta-analysis of eight epidemio-
logic studies. J. Natl. Cancer Inst. 89:4957
80. Lubin JH, Boice JD Jr, Edling C, Hornung RW, Howe G, et al. 1994. Lung Cancer Following Radon
Exposure Among Underground Miners: A Joint Analysis of 11 Studies. Rep. NIH Publ. No. 943644.
Washington, DC: US GPO
81. Ly KN, Xing J, Klevens RM, Jiles RB, Ward JW, Holmberg SD. 2012. The increasing burden of
mortality from viral hepatitis in the United States between 1999 and 2007. Ann. Intern. Med. 156:27178
82. Lynch BM. 2010. Sedentary behavior and cancer: a systematic review of the literature and proposedbiological mechanisms. Cancer Epidemiol. Biomark. Prev. 19:2691709
83. Martinez ME, Giovannucci E, Spiegelman D, Hunter DJ, Willett WC, Colditz GA. 1997. Leisure-time
physical activity, body size, and colon cancer in women. Nurses Health Study Research Group. J. Natl.
Cancer Inst. 89:94855
84. McCormack VA, Boffetta P. 2011. Todays lifestyles, tomorrows cancers: trends in lifestyle risk factors
for cancer in low- and middle-income countries. Ann. Oncol. 22:234957
85. McTiernan A, Kooperberg C, White E, Wilcox S, Coates R, et al. 2003. Recreational physical activity
and the risk of breast cancer in postmenopausal women: the Womens Health Initiative Cohort Study.
JAMA 290:133136
86. McTiernan A, Ulrich C, Slate S, Potter J. 1998. Physical activity and cancer etiology: associations and
mechanisms. Cancer Causes Control9:487509
87. Mellstedt H. 2006. Cancer initiatives in developing countries. Ann. Oncol. 17(Suppl. 8):viii243188. Menzler S, Piller G, Gruson M, Rosario AS, Wichmann HE, Kreienbrock L. 2008. Population at-
tributable fraction for lung cancer due to residential radon in Switzerland and Germany. Health Phys.
95:17989
89. Morgenstern H. 2008. Attributable fractions. In Encyclopedia of Epidemiology, ed. S Boslaugh, pp. 5563.
Thousand Oaks, CA: Sage
90. Muir CS, Nectoux J. 1982. International patterns of cancer. In Cancer Epidemiology and Prevention, ed.
D Schottenfeld, JF Fraumeni Jr, pp. 11937. Philadelphia, PA: WB Saunders. 1st ed.
91. Natl. Counc. Radiat. Prot. Meas. 2009. Ionizing Radiation Exposure of the Population of the U.S.: Recom-
mendations of the NCRP&M Rep. 160. Bethesda, MD: Natl. Counc. Radiat. Prot. Meas.
92. Natl. Res. Counc. 1986. Environmental Tobacco Smoke. Washington, DC: Natl. Acad. Press
93. Natl. Res. Counc. 1999. Health Effects of Exposure to Radon. Biological Effects of Ionizing Radiation (BEIR)
VI. Washington, DC: Natl. Acad. Press94. Palipudi KM, Gupta PC, Sinha DN, Andes LJ, Asma S, McAfee T. 2012. Social determinants of health
and tobacco use in thirteen low and middle income countries: evidence from Global Adult Tobacco
Survey. PLoS One 7:e33466
95. Parkin DM. 2006. The global health burden of infection-associated cancers in the year 2002. Int. J.
Cancer118:303044
96. Parkin DM. 2011. 1. The fraction of cancer attributable to lifestyle and environmental factors in the UK
in 2010. Br. J. Cancer105(Suppl. 2):S25
www.annualreviews.org Risk Factors and Global Cancer Burden 115
7/27/2019 ARPH Schottenfeld Final
20/25
97. Parkin DM. 2011. 2. Tobacco-attributable cancer burden in the UK in 2010. Br. J. Cancer105(Sup
2):S613
98. Parkin DM. 2011. 11. Cancers attributable to infection in the UK in 2010. Br. J. Cancer 105(Sup
2):S4956
99. Parkin DM, Boyd L, Walker LC. 2011. 16. The fraction of cancer attributable to lifestyle and enviro
mental factors in the UK in 2010. Br. J. Cancer105(Suppl. 2):S7781
100. Pischon T, Nothlings U, Boeing H. 2008. Obesity and cancer. Proc. Nutr. Soc. 67:12845
101. Polednak AP. 2008. Estimating the number of U.S. incident cancers attributable to obesity and t
impact on temporal trends in incidence rates for obesity-related cancers. Cancer Detect. Prev. 32:190102. Pomp D, Nehrenberg D, Estrada-Smith D. 2008. Complex genetics of obesity in mouse models. Ann
Rev. Nutr. 28:33145
103. Poschl G, Seitz HK. 2004. Alcohol and cancer. Alcohol39:15565
104. Powles T, Robinson D, Stebbing J, Shamash J, Nelson M, et al. 2009. Highlyactiveantiretroviral thera
and the incidence of non-AIDS-defining cancers in people with HIV infection. J. Clin. Oncol. 27:884
105. Preston DL, Kusumi S, Tomonaga M, Izumi S, Ron E, et al. 1994. Cancer incidence in atomic bom
survivors. Part III. Leukemia, lymphoma and multiple myeloma, 19501987. Radiat. Res. 137:S6897
106. Reis JP, Araneta MR, Wingard DL, Macera CA, Lindsay SP, Marshall SJ. 2009. Overall obesity an
abdominal adiposity as predictors of mortality in U.S. White and black adults.Ann. Epidemiol. 19:134
107. Renehan AG, Soerjomataram I, Leitzmann MF. 2010. Interpreting the epidemiological evidence linki
obesity and cancer: a framework for population-attributable risk estimations in Europe. Eur. J. Can
46:258192108. Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. 2008. Body-mass index and incidence
cancer: a systematic review and meta-analysis of prospective observational studies. Lancet371:56978
109. Roberts DL, Dive C, Renehan AG. 2010. Biological mechanisms linking obesity and cancer risk: n
perspectives. Annu. Rev. Med. 61:30116
110. Rockhill B, Newman B, Weinberg C. 1998. Use and misuse of population attributable fractions. Am
Public Health 88:1519
111. Rosso S, Zanetti R, Pippione M, Sancho-Garnier H. 1998. Parallel risk assessment of melanoma a
basal cell carcinoma: skin characteristics and sun exposure. Melanoma Res. 8:57383
112. Rowland RE, Stehney AF, Lucas HF Jr. 1978. Dose-response relationships for female radium d
workers. Radiat. Res. 76:36883
113. Rushton L, Bagga S, Bevan R, Brown TP, Cherrie JW, et al. 2010. Occupation and cancer in Brita
Br. J. Cancer102:142837114. Sachs RK, Brenner DJ. 2005. Solid tumor risks after high doses of ionizing radiation. Proc. Natl. Aca
Sci. USA 102:1304045
115. Samad AK, Taylor RS, Marshall T, Chapman MA. 2005. A meta-analysis of the association of physi
activity with reduced risk of colorectal cancer. Colorectal Dis. 7:20413
116. Schottenfeld D, Beebe-Dimmer J. 2006. Alleviating the burden of cancer: a perspective on advanc
challenges, and future directions. Cancer Epidemiol. Biomark. Prev. 15:204955
117. Schottenfeld D, Beebe-Dimmer J. 2006. Chronic inflammation: a common and important factor in t
pathogenesis of neoplasia. CA Cancer J. Clin. 56:6983
118. Schottenfeld D, Fraumeni JF Jr. 2006. Cancer Epidemiology and Prevention. New York: Oxford Un
Press. 3rd ed.
119. Schulman JM,Fisher DE.2009.Indoor ultraviolet tanning andskincancer: healthrisksand opportuniti
Curr. Opin. Oncol. 21:14449120. Secretan B, Straif K, Baan R, Grosse Y, El Ghissassi F, et al. 2009. A review of human carcinogens. P
E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol. 10:103334
121. Seitz HK, Stickel F, Homann N. 2004. Pathogenetic mechanisms of upper aerodigestive tract cancer
alcoholics. Int. J. Cancer108:48387
122. Sharma S, Kelly TK, Jones PA. 2010. Epigenetics in cancer. Carcinogenesis31:2736
123. Siemiatycki J, Richardson L, Straif K, Latreille B, Lakhani R, et al. 2004. Listing occupational carcin
gens. Environ. Health Perspect. 112:144759
116 Schottenfeld et al.
7/27/2019 ARPH Schottenfeld Final
21/25
124. Silverberg E. 1980. Cancer statistics, 1980. CA Cancer J. Clin. 30:2338125. Simard EP, Ward EM, Siegel R, Jemal A. 2012. Cancers with increasing incidence trends in the United
States: 1999 through 2008. CA Cancer J. Clin. 62:11828126. Slattery ML, Edwards SL, Ma KN, Friedman GD, Potter JD. 1997. Physical activity and colon cancer:
a public health perspective. Ann. Epidemiol. 7:13745127. Smith-Bindman R. 2010. Is computed tomography safe? N. Engl. J. Med. 363:14128. Srikanthan P, Seeman TE, Karlamangla AS. 2009. Waist-hip-ratio as a predictor of all-cause mortality
in high-functioning older adults. Ann. Epidemiol. 19:72431129. Steenland K, Burnett C, Lalich N, Ward E, Hurrell J. 2003. Dying for work: the magnitude of US
mortality from selected causes of death associated with occupation. Am. J. Ind. Med. 43:46182130. The NS, Suchindran C, North KE, Popkin BM, Gordon-Larsen P. 2010. Association of adolescent
obesity with risk of severe obesity in adulthood. JAMA 304:204247131. Thun MJ, Day-Lally C, Myers DG, Calle EE, Flanders WD, et al. 1997. Trends in tobacco smoking
and mortality from cigarette use in Cancer Prevention Studies I (19591965) and II (19821988). In
Smoking and Tobacco Control: Change in Cigarette-Related Disease Risks and Implication for Prevention and
Control, ed. DM Burns, I Garfinkel, JM Samet, pp. 30582. Bethesda, MD: Natl. Cancer Inst. Monogr.
8, NIH Publ. No. 974213132. Thune I, Furberg AS. 2001. Physical activity and cancer risk: dose-response and cancer, all sites and
site-specific. Med. Sci. Sports Exerc. 33:S53050133. Thune I, Lund E. 1996. Physical activity and risk of colorectal cancer in men and women. Br. J. Cancer
73:113440
134. Tucker MA. 2009. Melanoma epidemiology. Hematol. Oncol. Clin. North Am. 23:38395, vii135. UN. 2008. United Nations Scientific Committee on the Effects of Ionizing Radiation. 2006 Report to the General
Assembly. New York: UN136. van der Pols JC, Williams GM, Pandeya N, Logan V, Green AC. 2006. Prolonged prevention of squa-
mous cell carcinoma of the skin by regular sunscreen use. Cancer Epidemiol. Biomark. Prev. 15:254648137. van Kruijsdijk RC, van der Wall E, Visseren FL. 2009. Obesity and cancer: the role of dysfunctional
adipose tissue. Cancer Epidemiol. Biomark. Prev. 18:256978138. Vineis P, Xun W. 2009. The emerging epidemic of environmental cancers in developing countries. Ann.
Oncol. 20:20512139. Voelz GL, Lawrence JN, Johnson ER. 1997. Fifty years of plutonium exposure to the Manhattan Project
plutonium workers: an update. Health Phys. 73:61119140. Waki H, Tontonoz P. 2007. Endocrine functions of adipose tissue. Annu. Rev. Pathol. Mech. Dis. 2:3156141. Walker N, Grassly NC, Garnett GP, Stanecki KA, Ghys PD. 2004. Estimating the global burden of
HIV/AIDS: What do we really know about the HIV pandemic? Lancet363:218085142. Waterhouse J, Muir CS, Correa P, Powell J, eds. 1976. Cancer Incidence in Five Continents, Vol. III. Lyon,
Fr: IARC Sci. Publ. 15143. Wei EK, Colditz GA, Giovannucci EL, Fuchs CS, Rosner BA. 2009. Cumulative risk of colon cancer
up to age 70 years by risk factor status using data from the Nurses Health Study. Am. J. Epidemiol.
170:86372144. Weiss HA,DarbySC, Doll R. 1994. Cancer mortalityfollowingX-ray treatmentfor ankylosing spondyli-
tis. Int. J. Cancer59:32738145. Wertheim BC, Martinez ME, Ashbeck EL, Roe DJ, Jacobs ET, et al. 2009. Physical activity as a deter-
minant of fecal bile acid levels. Cancer Epidemiol. Biomark. Prev. 18:159198146. Wolin KY, Yan Y, Colditz GA, Lee IM. 2009. Physical activity and colon cancer prevention: a meta-
analysis. Br. J. Cancer100:61116
147. World Cancer Res. Fund/Am. Inst. Cancer Res. 2009. Policy and Action for Cancer Prevention: Food,Nutrition, and Physical Activity: A Global Perspective. Washington, DC: Am. Inst. Cancer Res.
148. World Health Organ. (WHO). 2000. World Health Organization: Obesity: Preventing and Managing the
Global Epidemic. WHO Tech. Rep. Ser. 894. Geneva, Switz.: WHO149. World Health Organ. (WHO). 2007. Attributable Causes of Cancer in France in the Year 2000. Lyon, Fr.:
IARC150. Zhang C, Rexrode KM, van Dam RM, Li TY, Hu FB. 2008. Abdominal obesity and the risk of all-cause,
cardiovascular, and cancer mortality: sixteen years of follow-up in US women. Circulation 117:165867
www.annualreviews.org Risk Factors and Global Cancer Burden 117
7/27/2019 ARPH Schottenfeld Final
22/25
Annual Review of
Public Health
Volume 34, 2013 Contents
Symposium: Developmental Origins of Adult Disease
Commentary on the Symposium: Biological Embedding, Life Course
Development, and the Emergence of a New Science
Clyde Hertzman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p
From Developmental Origins of Adult Disease to Life Course Research
on Adult Disease and Aging: Insights from Birth Cohort Studies
Chris Power, Diana Kuh, and Susan Mortonp p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p
Routine Versus Catastrophic Influences on the Developing Child
Candice L. Odgers and Sara R. Jaffee p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p
Intergenerational Health Responses to Adverse and
Enriched Environments
Lars Olov Bygren p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p
Epidemiology and Biostatistics
Commentary on the Symposium: Biological Embedding, Life CourseDevelopment, and the Emergence of a New Science
Clyde Hertzman p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p
From Developmental Origins of Adult Disease to Life Course Research
on Adult Disease and Aging: Insights from Birth Cohort Studies
Chris Power, Diana Kuh, and Susan Morton p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p
Causal Inference in Public Health
Thomas A. Glass, Steven N. Goodman, Miguel A. Hernan,
and Jonathan M. Samet p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p
Current Evidence on Healthy Eating
Walter C. Willett and Meir J. Stampfer p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p
Current Perspective on the Global and United States Cancer Burden
Attributable to Lifestyle and Environmental Risk Factors
David Schottenfeld, Jennifer L. Beebe-Dimmer, Patricia A. Buffler,
and Gilbert S. Omenn p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p
viii
7/27/2019 ARPH Schottenfeld Final
23/25
The Epidemiology of Depression Across Cultures
Ronald C. Kessler and Evelyn J. Bromet p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p