ARPH Schottenfeld Final

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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

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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.


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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


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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



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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).



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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



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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



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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



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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


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



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



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



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).



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



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%


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.

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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

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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


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The Epidemiology of Depression Across Cultures

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