Prevention of tumors

C H A P T E R

8 Prevention of tumors O U T L I N E 8.1 Confirmed human carcinogens: preventative measures 212 8.1.1 Deriving from early work on occupational cancers 212 (a) Arsenic 212 (b) Polyaromatic hydrocarbons especially in tars and mineral oils 212 (c) Chemical dyes 212 (d) Ionizing radiations: uranium miners 214 (e) Mixed radiations: radium poisoning 214 (f) Ionizing radiations: thorium dioxide (Thorotrast) 215 8.1.2 The beginnings of “environmental carcinogenesis”: leaked and dumped industrial and nonindustrial chemicals: the work of W. C. Hueper 215 8.1.3 Reduced exposure to amphibole (mainly “blue” and “brown”) kinds of asbestos 219 8.1.4 Reduction in tobacco usage 219 8.1.5 Sunscreen lotions for the reduction skin cancers 219 8.1.6 Vinyl chloride 220

Principles of Tumors https://doi.org/10.1016/B978-0-12-816920-9.00008-0

209

8.1.7 Immunization against human papilloma viruses in the prevention of cervical cancer 221 8.1.8 Attempts to reduce transmission of the human immunodeficiency virus in the prevention of Kaposi’s sarcoma and other HIV-related malignancies221 8.2 Identifying and investigating further carcinogens: epidemiological data and methods 221 8.2.1 Data specifications 221 (a) General 221 (b) Self-reported data 222 (c) Biodata 223 (d) Concurrent anticarcinogens have rarely been studied 223 8.2.2 Complexities of geographical/cultural/ ethnic factors 223 8.2.3 Cross-sectional studies 224 8.2.4 Cohort studies: finding changing incidences of disease 225 8.2.5 Case-controlled studies 225 8.2.6 Interventional studies 225 8.3 Association does not prove causation 8.3.1 General 8.3.2 Bradford Hill’s guidelines

225 225 225

Copyright © 2020 Elsevier Inc. All rights reserved.

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8.4 Other aspects of interpreting cancercausation epidemiological data 227 8.4.1 Importance of finding factors least associated with others 227 8.4.2 Use of “risk” for associations 227 8.4.3 Classification of “risk”/association: absolute risk, difference in absolute risk, relative risk, and odds ratio 228 (a) Absolute risk 228 (b) Difference in absolute risk 228 (c) Relative risk 228 (d) Odds ratio 228 8.4.4 Attribution of fractions of “risk” 228 8.5 Problematic issues with low-level or disputed carcinogens and carcinogenic factors 229 8.5.1 Aging and background radiation enhancing “normal” rates of mutation 229 8.5.2 Air pollution 229 8.5.3 Lung cancer in never-smokers 230 8.5.4 Water pollution, chlorination 230 8.5.5 Low dose exposure to chrysotile and bronchogenic lung cancer 230 (a) Pulmonary and mesothelial tumors 230 (b) Other cancers 230 (c) Particular properties of chrysotile asbestos 230 8.5.6 Affected family members 230 8.5.7 Alcohol consumption 230 8.5.8 Caffeine, especially in coffee 231 8.5.9 Pharmaceuticals, other health-related products, talc 231 8.5.10 Glyphosate 231 8.5.11 Red meat 232 8.5.12 “Poor diet” and “fiber” 232 (a) Definition of “poor diet” 232 (b) Diets with a low component of vegetable fiber (cellulose) and prevention of carcinomas of the colon and rectum 233

8.5.13 The World Cancer Research Fund/ American Institute for Cancer Research studies 233 (a) Diet 233 (b) Lack of physical exercise 234 (c) Obesity 234 8.5.14 Gut flora 235 8.5.15 Acrylonitrile 235 8.5.16 Wood dust 235 8.6 Laboratory methods in the identification of environmental carcinogens 235 8.6.1 Background 235 8.6.2 Tumors in animals 235 8.6.3 Enhanced rates of malignant transformation in cells cultured in vitro 237 (a) Methodological issues 237 (b) Advantages 239 8.6.4 Other genopathic phenomena used for testing potential carcinogenicity 239 (a) In living animals 239 (b) In cultured cells 239 (c) Tests in bacteria 240 (d) Other tests 241 8.6.5 Multiplicity of tests and methods for their use 241 8.6.6 Co-carcinogens and other multifactorial circumstances 242 8.6.7 Noncorrelation of relative potencies for carcinogenesis in relation to other effects 242 8.6.8 Possible future experimental methods 243 8.7 Human lesion and genetic screening programs and their efficacies in preventing deaths from tumors 8.7.1 Overview 8.7.2 For carcinoma of the bronchi 8.7.3 For colorectal carcinoma 8.7.4 For carcinoma of the breast 8.7.5 For carcinoma of the prostate 8.7.6 For carcinoma of the cervix

243 243 243 244 244 244 245

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8.7.7 Other biomarker or lesional screening 8.7.8 Screening for germline genetic predispositions/personalized disease prevention through genomic studies (a) Selective gene sequencing 8.7.9 Assessing benefits of screening 8.7.10 Harms of screening

245

246 246 246 247

8.8 Cancer-preventative drugs: benefits and potential dangers 247 8.8.1 General 247 8.8.2 Difficulties in assessing complex mixtures 248 8.8.3 Classification of cancer-preventative drugs 248 (a) Preventing carcinogens reaching susceptible cells 248 (b) Preventing “maturation” of susceptible cells 248 (c) “Suppressive agents” 249 8.8.4 Laboratory assessments of these agents 250 8.8.5 Difficulties of clinical trials of these agents 250

Prevention is the major benefit which scientific studies of disease can provide. In general, preventive measures are most successful when a definite cause of a disease is known. Some chemicals in occupational settings, radiations, tobacco in all the ways it is used, together with a few biological agents are well-established causes of a few types of tumors (see in Chapter 7). However, currently the causes of most tumors are not known. On the assumption that most, if not all, cancers not associated with a known external cause must be due to some unknown external agent(s), most current preventative efforts are directed at identifying these assumed unknown external carcinogens. It is thought that they access

8.8.6 Currently recommended cancerpreventative drugs for particular tumor types (a) Lung carcinoma (b) Breast carcinoma (c) Colorectal carcinoma (d) Prostatic carcinoma 8.9 Barriers to prevention 8.9.1 Lack of information 8.9.2 Failure to access or act on information

250 250 250 251 251 251 251 251

8.10 Summary of translational issues in cancer prevention 252 8.10.1 Lack of data on mutation accumulation over lifetimes of individuals 252 8.10.2 Lack of data on bioaccumulations 252 (a) Maximum permissible exposures/“levels” 252 8.10.3 Vagueness in the biology and mutagenic implications of “lifestyle” factors 252 8.10.4 Data currently unavailable 252 References

253

humans through the air, water, foods obtained from the environment, or from aspects of lifestyles [1]. The effort to identify external carcinogens is reflected in the volume of literature in the recent public and medical media. A search “Cause of Cancer” in the archive of a prominent New York newspaper from March 2008 to March 2018 yielded more than 6000 articles. A search of Amazon books “Cause of Cancer” yielded 202 current offerings. A search of PubMed for “etiology cancer” yielded 1,567,545 articles of which 209,090 were reviews. This chapter gives an overview of many of the confirmed and contentious issues in

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prevention of tumors. It is based on the principle of a five-step scheme described in Chapter 7, especially that (i) tumors can arise without external agents due to inherent error rates in DNA-enzymatic processes, possibly affected by radiations from internal 40K, 14C, and 48Ca or cosmogenic isotopes such as 22Na (see Section 8.5 below) [2] and (ii) carcinogens have their effects by enhancing the errors in DNA-related processes, rather than by any different mechanism. Section 8.6 is included to illuminate the contributions and difficulties of laboratory studies in establishing the appropriateness of interventions in the population for the prevention of tumors.

8.1 Confirmed human carcinogens: preventative measures This section reviews known carcinogens for humans, and the circumstances through which they are believed to cause human tumors. Some have been mentioned in Chapter 3 in discussion of parent cell specificity to carcinogenic effects of agents (Fig. 8.1).

8.1.1 Deriving from early work on occupational cancers (a) Arsenic This metalloid exists in nature mainly as oxides. In high doses, it has been used as a poison from Ancient Rome onward [3]. In the 18th century, it was proposed in low doses as a therapeutic agent (e.g., Fowler’s solution) [4]. In the 19th century, arsenical compounds were introduced as pesticides, antibiotics, and anticancer drugs. In 1822, it was suggested to be a carcinogen in horse skin [5], and in 1888, Hutchinson associated inorganic arsenic medication with human skin cancer [6]. Subsequent studies showed it can cause

cancers of the lung and other sites in humans. Its carcinogenic potency in laboratory animals is unclear [7]. Arsenic has been withdrawn from domestic use in Western countries, but arsenical pesticides are used in some Asian countries. (b) Polyaromatic hydrocarbons especially in tars and mineral oils Beginning with being Percivall Pott’s, 1775, description of scrotal cancer in chimney sweeps [8], similar skin cancers were found to occur in a several other occupationsdsuch as shale oil mining, petroleum processing, and factory work where mineral oils were used for lubricating machinery [9] (Figs. 8.2e8.4). During the period 1915e18, Japanese scientists discovered that painting the ears of rabbits and mice with coal tar extracts produced tumors, some of which were malignant [10]. Starting in 1922, research to find the coal tar carcinogen by a team of British chemists at the Institute of Cancer Research in London culminated in the synthesis in 1930 of the first pure chemical compounds to demonstrate carcinogenic activity, dibenz[a, h]anthracene (DBA), XXV, and its 3-methyl derivative. After distilling and fractionating two tons of pitch from a “Gas, Light, and Coke Company,” they ultimately isolated several grams of two C20H12 polycyclic aromatic hydrocarbons. Three years later, Cook and coworkers (1933) synthesized for the first time benzo[a]pyrene and benzo[e]pyrene and proved them identical to these two “coal tar PAHs.” Ultimate confirmation of the carcinogenicity of BaP came when all five survivors of a group of 10 mice whose backs had been painted with synthetic BaP developed tumors; BeP was not carcinogenic [11]. Preventative measures, such as providing baths and soap for miners at the pit heads, were slowly introduced in the 20th century. (c) Chemical dyes In the late 19th and early 20th centuries, there were many clinical reports of what came to be

8.1 Confirmed human carcinogens: preventative measures

A.

Based on known carcinogens

B.

213

Based on pre-malignant condions

Idenfy the carcinogen Idenfy pre-malignant cells If possible: remove agent from the environment

If not possible to remove agent from environment: prevent access to the body

If not possible to prevent access to the body: adopt chemo-preventave measures

Ablate pre-malignant cells

Carry out clinical follow-up in case of further lesions

If a virus, use vaccines if available

C.

Based on genec predisposions

Idenfy the germ-line mutaon

Offer prophylacc ssue or organ removal

D. Based on chemoprevenon

Idenfy the parcular premalignant circumstance

Offer drugs if any approved drug is available

FIGURE 8.1 Overview of the prevention of tumors.

called “aniline tumors of the bladder” in workers engaged in the manufacture and use of chemical dyes. The progenitor of many retrospective cohort studies in occupations was the “field survey” of tumors of the urinary bladder conducted by Case et al. (1954) in the British chemical industry. Among workers employed since 1920 for more than 6 months in the manufacture of aniline, benzidine, alpha-naphthylamine (ANA), or beta-naphthylamine (BNA), 341 cases of bladder cancer occurred, 298 (87%) of which were in

workers who had contact with one of the chemicals: 127 of the latter died of the disease, whereas 4 would have been expected based on national mortality data (R 32). There was no external source of data from which the expected number of incidence cases could be computed [12]. Experimental testing demonstrated that many dyes could be carcinogenic in animals (admittedly in very high doses), while no evidence for their carcinogenicity in humans could be shown. For example, “butter yellow” (4-

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FIGURE 8.4 Shale oil mining, early 20th century, Scotland. Source: BP Archive. https://www.geoexpro.com/articles/ 2014/11/-what-oilfields-onshore-oil-in-the-uk.

FIGURE 8.2 Percivall Pott (1714-1788) engraved from an original picture by Nathaniel Dance-Holland - Published by Edward Hedges, London, 1785. Source: Public Domain, https://commons.wikimedia.org/w/index.php?curid29774268.

dimethylaminoazobenzene) was used as a dye for coloring polishes, wax products, polystyrene, and soap and was also used as a pH indicator. In rats, it is activated in the liver in association with causing tumors in that organ as well as lung and bladder. No evidence is available for any chronic (long term), reproductive, developmental, or carcinogenic effects in humans [13]. (d) Ionizing radiations: uranium miners Skin cancers and leukemia were noted among the pioneers of radiation physics from 1902. Animal studies beginning in the 1900s confirmed the carcinogenic effects of radiations [14]. In uranium miners, excess incidence of lung tumors was recognized from 1944 [15]. The cancers were presumably due to direct inhalation of dust containing uranium or its solid decay product radium. To this would be added inhaled 222radon (a gas decayeproduct of radium), which collected in the depths of the mine shafts (Fig. 8.5). (e) Mixed radiations: radium poisoning 226

FIGURE 8.3 John Colfer - A chimney sweep in 1850, Wexford, Ireland. By Unidentified photographer - Unknown. Source: Public Domain, https://commons.wikimedia.org/w/index. php?curid238.

Radium emits light, as well as alpha and gamma rays. 80% of the ingested radium leaves the body through the feces, while the other 20% goes into the bloodstream, mostly accumulating in the bones [16]. From 1917 to 1926, radium was incorporated into luminous paints and used particularly to

8.1 Confirmed human carcinogens: preventative measures

238 92 4.5 Gy

U

α

 

–

234 90 24.1 d

Th

Pa

–

234 92 245.5 ky

U

215

Uranium

Protacnium

α 230 90 75.38 ky

Th

Thorium

Ra

Radium

Rn

Radon

α

α

Astane

Polonium

Bismuth

Lead

Thallium

Mercury

α

At

–

218 84 3.1 min

Po

α

–

214 82 26.8 min

Pb

FIGURE 8.6 Clock dial painting with radium. Source: Telegraph newspaper UK via Web from review of Moore K. The radium girls. London: Simon & Schuster; 2017. https://www. telegraph.co.uk/books/what-to-read/the-forgotten-factory-girlskilled-by-radioactive-poisoning/.

α



–

214 83 19.9 min

Bi

α

TI

Po

α

–

210 81 1.3 min

214 84 164.3 μs

 –

210 82 22.2 y

Pb

α

–

–

210 83 5.01 d

Bi

α

210 84 138 d

Po

α

–

206 82 Stable

Pb

206 81 4.2 min

TI

Hg

FIGURE 8.5 Decay series of uranium significant to human disease. Source: Tosaka - File: Decay chain (4nþ2, Uranium series). PNG, CC BY 3.0, https://commons.wikimedia.org/w/index. php?curid33293646.

paint the arms and numerals of watch dials so that the dial could be read at night. As part of the painting technique, the employees were instructed to “point” the brushes using their mouths, becoming contaminated with the radium in the process. Bone necrosis and fractures, as well as bone marrow failure and ultimately bone sarcomas and other cancers, developed (Figs. 8.6 and 8.7). (f) Ionizing radiations: thorium dioxide (Thorotrast) Thorotrast, an X-ray contrast medium consisting of thorium dioxide, was introduced in 1928 and used extensively in Western countries and Japan. Thorium is a decay product of uranium

(see above) and an alpha-ray (helium nuclei) emitter. It consists of 99.98% 232Th, which has a half-life of 1.4
1010 years. The remainder is essentially 230Th which has a half-life of 75,000 years [17]. The agent was injected intravenously or intraarterially and, in 1934, was shown to produce sarcomas at injection sites in rats [18]. Human hepatic angiosarcomas in patients receiving the material were described from 1947 [19]. The carcinogenic aspect of the substance may be partly due to the chemical nature of thorium dioxide [20].

8.1.2 The beginnings of “environmental carcinogenesis”: leaked and dumped industrial and nonindustrial chemicals: the work of W. C. Hueper Most tumors are not associated with employment in chemical plants or in industries using chemicals or in strong relation to any obvious habit- or lifestyle factor apart from tobacco use. In the mid-20th century, it was suggested that nonoccupational tumors might be caused by industrial chemicals, especially newly synthesized ones, which were being released into the environment from plants where the chemicals were produced and the factories where they were used.

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PERCENT OF EXPOSED PERSONS WITH BONE SARCOMAS

100 80 60 40 0.0046% PER RAD

20 0 0

4000 8000 12,000 AVERAGE SKELETAL DOSE IN RADS

16,000

FIGURE 8.7 Correlation of bone sarcomas and radiation dose from radium ingestion. Source: Fig 4-4 in Health Risks of Radon and Other Internally Deposited Alpha-Emitters: Beir IV. National Research Council (US) Committee on the biological effects of ionizing radiations. Washington (DC): National Academies Press (US); 1988 https://www.ncbi.nlm.nih.gov/books/NBK218126/.

The main early proponent of the idea was Wilhelm C. Hueper (1894e1978), a native of Schwerin, Mecklenburg, Germany, who graduated in medicine in 1920, and emigrated to the United States in 1923. First, he practiced as a pathologist, and in the 1930s, he worked for Dupont as an industrial hygienist. In 1942, he was principal pathologist at the Warner Institute for Therapeutic Research, New York, a division of William R Warner Inc, pharmaceutical manufacturer. In 1908, the company had been acquired by Gustavus A. Pfeiffer & Company, a patent medicine company from St. Louis, MO, United States. Pfeiffer retained the Warner company name and moved headquarters to New York; by 1940s, some 50 companies had been acquired including Richard Hudnut Company (1916) and the DuBarry cosmetic company [21]. In 1942, Hueper published his first major book “Occupational Tumors and Allied Diseases” [22]. Chapter 1 Section 1 “The new artificial environment” explains his basic concept: that industrialization was causing “a revolutionary change in our inanimate external environment .” with “. numerous artificial heretofore exogenous factors .” potentially causing “. chronic and insidious diseases never observed before” ([22], pp. 3e10).

The remainder of the book describes known occupational diseases, with attempts to minimize the effects of “lifestyle factors.” For example, he stated While chronic alcoholism is incriminated in the production of hepatic cirrhosis, more recent clinicstatistical and experimental evidence has done much to discredit this conception ([22], p. 347).

Tobacco smoking as a cause of lung, oropharyngeal, and laryngeal cancers is noted in half a page as The tobacco smoking habit provides an additional source through which tarry substances of known carcinogenic quality may enter the respiratory system ([22], p. 426).

He noted papers from 1932 onward linking the habit with the cancers, without comment. For almost every tumor type for which no exposure to industrial chemical or other cause was apparent, he invoked mechanical or other trauma as causes. Hueper continued with these themes in two articles on the topic in 1947 and in “Environmental and Occupational Cancer” (1948) [23]. In this work, tobacco was mentioned in relation to cancers of the lip, mouth, and upper respiratory tract (23, ps 14, 29 and 30), but not of the

217

8.1 Confirmed human carcinogens: preventative measures

lung. Trauma was discussed as a cause of cancer ([23], p. 31) (Fig. 8.8). Hueper obfuscated the importance of tobacco smoking on the grounds of intercountry differences in incidence:

for the remarkable increase in lung cancer frequency and for the causation of a major portion of lung cancers, industrial and industry-related carcinogens would well fit this pattern since the growth of industrial establishments and the use of their products in the economic life of different countries have greatly lacked uniformity in time, type and extent.

Considering the recorded strikingly irregular epidemiological behavior of lung cancer in different countries, states, provinces, communities, and population groups, it is obvious that this pattern scarcely corresponds with the pattern presented by the degree and spread of the cigarette smoking habit. If the action of environmental carcinogens other than those possibly contained in cigarette smoke should mainly account

7

6

This concept receives support from a critical evaluation of the data on the sex distribution of lung cancers, the changes in the sex ratio during recent decades, and the probable reasons underlying at least a part of these phenomena (Tables 11 and 12). Considering the remarkable variations which the malefemale ratio of lung cancers has shown at different

PRODUCT

–

1.

BITUMINUS COAL

-

PRODUCTION IN U.S., MILLIONS OF NET TONS

UNIT

2.

FUEL BRIQUETS

-

TOTAL PRODUCTION, THOUSANDS OF NET TONS

3.

CARBON BLACK

-

PRODUCTION IN MILLIONS OF POUNDS

4.

PETROLEUM

-

PRODUCTION OF CRUDE PETROLEUM, MILLIONS OF BARRELS

5.

PETROLEUM, ASPHALT

-

PRODUCTION OF ASPHAL T (FROM PET ROLEUM), THOUSANDS OF SHORT TONS

6.

COAL TAR

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PRODUCTION, - THOUSANDS OF GALLONS

7.

ISOPROPANOL

-

PRODUCTION, - THOUSANDS OF POUNDS

8.

ASBESTOS

-

APPARENT CONSUMPTION, THOUSANDS OF SHORT TONS, (M YRBK-1939)

9.

ARSENIC

-

PRODUCTION AND IMPORTS, THOUSANDS OF SHORT TONS

10.

CHROMITE

-

TOTAL SUPPLY, THOUSANDS OF TONS

1

3

SOURCE-MINERALS YEARBOOK, 1945

8 2 10 5

5

4 Units

4

7 6

9 3

2

1

1900

1905

1910

1915

1920

1925

1930

1935

1940

1945

1950

Environmental Causes of Cancer of the Lung

FIGURE 8.8

Figure by Hueper: tobacco consumption in several countries (1956). Source: A Quest into the Environmental Causes of Cancer of the Lung. Public Health Service Publication No. 452. Washington DC: US Government Printing Office; 1956. p. 9e10.

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8. Prevention of tumors

times, in different localities, and in different demographic groups, it is most unlikely that such discrepancies and changes are attributable to fluctuations in the intensity of one single factor, such as cigarette smoking [24].

Trauma was mentioned only in relation to beryllium entering the lung ([24], p. 31) (Fig. 8.9). In his last book (1964) with W. D. Conway, “Chemical Carcinogenesis and Cancer” [25], Hueper began, as in his earlier works with sections, “The artificial modern environment” and “The new cancer panorama,” declaring ([25], p. 17): (i) That the prevalence of cancers in the US population indicated “all the characteristics of an epidemic in slow motion” and (ii) That “through a continued, unrestrained, needless, avoidable and in part reckless increasing contamination of the human environment with carcinogens . the stage is being set for a future occurrence of an acute catastrophic epidemic” which once present could not be checked or its course appreciably altered.

(A)

10 9

ENGLAND & WALES MALES

8

U.S.A. MALES

7

NORWAY MALES

6

In the section on lung cancer ([25], pp. 141e145), he focused on new chemicals in the environment and down-played a role for cigarette smoking. He also discounted tobacco smoking as a cause of lung cancer, while reproducing data from Richard Doll showing the strength of the association. The rise in lung cancers coincides moreover, with the period when various carcinogenic aromatic chemicals .. entered the human economy. The total evidence . strongly incriminates chemical agents of various types and origins. The decision as to whether an agent has major or minor role . is at present a matter of scientific discussion, depending (paraphrase) not only on professional knowledge, experience and judgement . but on personal preference or prejudice” ([25], p. 145).

In the remainder of the book, Hueper found an occupational basis for tumors of almost every organ: skin, alimentary system, respiratory, urinary, hematolymphoid, mesenchymal, optic, neural, etc. Where no industrial chemical seemed likely, he invoked traumadespecially incurring

(B) Under 17

17–20

21–24

25 & Over

NORWAY FEMALES

5 4 3 2 1

SWITZERLAND MALES ENGLAND & WALES FEMALES

U.S.A. FEMALES SWITZERLAND

FEMALES 0 1924 1928 1932 1936 1940 1944 1948 1950

FIGURE 8.9 Hueper’s figures from his 1956 book demonstrating lung cancer deaths. (A) Comparative trends in respiratory cancer mortality in several countries, 1924e1950. (B) Age-adjusted death rates for respiratory cancer per 100,000 white males in the United Sates, 1950.

8.1 Confirmed human carcinogens: preventative measures

though occupationdas the cause. He dismissed tobacco smoking as a cause of lung cancer, in favor of inhaled diesel or petrol fumes, or the exhausts of engines which burnt them. He did not mention nonoccupational trauma as a cause of tumors. Hueper’s ideas entered the public arena with the book “Silent Spring” (1962) by Rachel Carson (1907e64) which began the current environmentalist movement [26].

8.1.3 Reduced exposure to amphibole (mainly “blue” and “brown”) kinds of asbestos This fire-proof fibrous mineral has been used for various purposes since ancient times. Its use increased enormously from the 1920s, but only in the 1950s did the numbers of cases of mesothelioma begin to rise and the relationship between asbestos exposure and the tumor type be recognized [27]. Since then, over several decades and involving extensive legal processes, amphibole asbestos has been banned in many western countries. Serpentine asbestos (“white”) is less carcinogenic, as discussed in Section 8.5.5 (below) (Fig. 8.10).

8.1.4 Reduction in tobacco usage Tobacco has been used in many ways for centuries [28]. The history of the recognition that

FIGURE 8.10

Workers in an asbestos sheet making plant, Sydney, Australia. Source: https://www.smh.com.au/business/ james-hardie-asbestos-compensation-scheme.

219

smoking tobacco causes lung cancer is mentioned in Section 8.1.2 above. Antitobacco statements and laws were made, but the first public awareness campaign was launched in Germany in the 1930s. Although the association between smoking and lung cancer was established by scientists there, these campaigns were set against the backdrop of the Nazi quest for bodily purity and clean living [29]. The association between smoking and lung cancer was known in Western Europe and the United States, but little publicity was given to the findings of the Doll and Hill Study of lung disease and smoking habits of doctors (The Doctors Study) [30,31]. The US Surgeon General’s report on the matter in 1964 stimulated numerous subsequent antitobacco campaigns, and tobacco consumptiondalong with lung cancer incidencedhas declined [32] (Fig. 8.11).

8.1.5 Sunscreen lotions for the reduction skin cancers Avoidance of excessive sun exposure by ointments or lotions, especially using zinc oxide, was a feature of recorded Ancient Mediterranean civilizations [33]. Synthetic UV blocking agents date from 1928. There are now at least 20 substances approved as sunscreens in various parts of the world. Many block UVB but not UVA, while others block both (“broad-spectrum” agents). Sunscreen use can help prevent melanoma [34e36] and squamous cell carcinoma [37]. There is little evidence that it is effective in preventing basal cell carcinoma [38]. The “SPF factor” is the inverse of the fraction of the incident UV which penetrates to the epidermis. Thus, if 1/15th of the UV penetrates the screen, the screen is given an SPF of “15.” In the 1960e70s, the dangers of sun exposure were paid little attention and having a skin tan was seen to be attractive by some

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8. Prevention of tumors

(A)

Male lung cancer death rate

Per Capita Cigaree Consumpon

5000

100

4500

90

4000

80

3500 3000

70

Per capita cigaree consumpon

60

2500

50

2000

40

1500

30

1000

20 Female lung cancer death rate

500

10 0

1900 1905 1910 1915 1920 1925 1930 1935 1940 1945 1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2005 2009

0

Lung Cancer Deaths per 100,000 persons

Trends in Tobacco Use and Lung Cancer Death Rates* in the US

*Age-adjusted to 2000 US standard populaon. Source: Death rates: US Mortality Data, 1960-2009, US Mortality Volumes, 1930-1959, Naonal Center for Health Stascs, Centers for Disease Control and Prevenon. Cigaree consumpon: US Department of Agriculture, 1900-2007.

(B)

Trends in Current Cigaree Smoking by High School Students* and Adults**— United States, 1965-2014 45

Students Adults**

40 35 Percent (%)

30 HP 2020 Goal

25

18.8% Youth 18%

20

16.7%

15

Adults 12%

10 5 0 1965 1968 1971 1974 1977 1980 1983 1986 1989 1992 1995 1998 2001 2004 2007 2010 2011 2012 2013 2014

2020

Year *Percentage of high school students who smoked cigarees on 1 or more of the 30 days preceding the survey (Youth Risk Behavior Survey, 1991-2013). **Percentage of adults who are current cigaree smokers (Naonal Health Interview Survey, 1965-2014).

FIGURE 8.11

Cigarette smoking in the United States. (A) Trends in tobacco use and lung cancer death rates in the United States. (B) Trends in current cigarette smoking by high school students and adults in the United States.

Europeans. However, as melanoma became more common, a national awareness campaign began in the United States in 1985 [39]. Similar programs have been developed in Australia and other countries where sunlight hours are long, and there is a significant European population.

8.1.6 Vinyl chloride In the last 50 years, a major incontrovertible finding was that vinyl chloride causes angiosarcoma (a rare malignancy) in humans. This compound is a gas that is polymerized to produce

8.2 Identifying and investigating further carcinogens: epidemiological data and methods

polyvinyl chloride, a widely used plastic. Cleaning polymerization chambers exposes workers to residual VC monomer. In 1971, it was shown to be carcinogenic in rats [40], and, in 1974, it was shown to be the cause of angiosarcomas of the liver in humans [41].

8.1.7 Immunization against human papilloma viruses in the prevention of cervical cancer The pathogenetic role of human papilloma viruses, especially types 16 and 18, in cervical carcinomas was established in the 1980s [42]. A vaccine based on a virus-like particle (VPL) of HPV was developed in the mid-2000s and has become used throughout the world [43]. Subsequent multi-VPL strain vaccine preparations have become available with improved results [44]. Optimum protocols for cervical screening and resource allocations remain an issue in control of the disease [45,46].

8.1.8 Attempts to reduce transmission of the human immunodeficiency virus in the prevention of Kaposi’s sarcoma and other HIV-related malignancies The human immunodeficiency virus (HIV) was identified in 1984, and the range of tumors arising in infected personsdKaposi sarcoma, non-Hodgkin lymphoma, and invasive cervical cancerdwere recognized in the following decades. From 1990 to 2014, the number of people living with HIV rose from 8 million to 36.9 million [47]. Numerous publicity campaigns concerning use of condoms during sexual intercourse and cleaning or nonreuse of needles by relevant populations seem to have had limited effect. Attempts to develop a vaccine against the virus have failed because in the living virus, the epitope of its envelope protein is concealed from the surface. New techniques to circumvent

221

this problem are being investigated [48], but the hypermutability of the virus remains another difficult problem (Figs. 8.12 and 8.13).

8.2 Identifying and investigating further carcinogens: epidemiological data and methods The results of epidemiological studies of factors associated with cancers are often divergent. Methodological issues in these studies may be important sources of the differences.

8.2.1 Data specifications (a) General For all kinds of epidemiological study, the whole population is usually divided into groups by sex, age, occupational, lifestyle, and other factors (see in Chapter 7). When applied to occupational studies, necessary aspects of the data include the following: (i) Accurately diagnosing the cases of the disease and hence reliably establishing the incidence in the different periods of time, (ii) Correctly separating out the subgroups within the overall group in which the tumor type is increased, (iii) Accurately determining the degree of exposure of individuals in that population to the suspected etiological factor(s). In any particular industry, employees in different activities in the industrydclerical, administrative, and ancillary staff as well as employees handling the putative carcinogensdmay have quite different degrees of exposure to agents than “factory floor” workers. Thus, the incidence of tumor in all the workers may be only slightly above average, but the incidence in the factory floor workers may be greatly in excess of the average for the whole population.

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FIGURE 8.12

8. Prevention of tumors

Trends in global incidence of human immunodeficiency virus infection. Source: https://ourworldindata.org/hiv-

aids.

(b) Self-reported data For lifestyle factors, usually only self-reported exposures to putative carcinogenic factors are documented. For example, the data on “pack years” of exposure to tobacco for each individual are derived from the statements of the individual subjects of the study. These statements are

FIGURE 8.13

usually not independently assessed. However, self-reported data are not always accurate indications of doses/exposures of individuals in populations to known or putative environmental carcinogens. In a given workforce, there may also be some encouragement to claim exposures if any tumor or other disease develops (see biases

AIDS diagnoses and deaths in United States and United Kingdom, 1985e2013. (A) AIDS diagnoses and deaths, United States. (B) AIDS diagnoses and deaths, United Kingdom.

8.2 Identifying and investigating further carcinogens: epidemiological data and methods

Chapter 20), because of possible later class actions or other litigation providing financial returns. (c) Biodata In some situations, it may be possible to collect bio-samples (blood, urine, feces, and less commonly tissue) from the population to measure transient or accumulated amounts of agent. These are particularly used in industrial studies [49,50], but also on tissues and proteins from a variety of tissues [51,52]. The data are independent of self- or other-person reports of exposures [53]. These methods are also valuable because they may provide accurate dose gradient data [54]. Thus, if a study is primarily about the possible carcinogenic effect of exposure to a chemical, and the chemical accumulates in the body, then the actual measurements of that accumulation is obviously important (see Section 8.1.3). In many surveys, the only samples available are of blood. Members of the general public are sometimes reticent about submitting to more invasive procedures, such as adipose tissue sampling. For arsenic exposure, skin, hair, and nails are the most valuable structures to assess this carcinogen [55]. Levels of tobacco derivatives can be measured in blood samples [56]. Pesticide exposure, for example, to organochlorines, can be measured in adipose tissue [57]. Tests of genetic damage to employees may be carried out. Examples are types of DNA damage or the modified lymphocyte micronucleus test [58]. Testing for other acquired genomic abnormalities, as for example, in bronchial epithelium in tobacco smokers [59], is rarely undertaken because of cost. Measurement of carcinogen molecular adducts is also an option [60,61]. (d) Concurrent anticarcinogens have rarely been studied It would clearly be desirable in epidemiologic studies of cancers to record concurrent exposures to anticarcinogens. However, because so few of these are reliably identified, studies of

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anticarcinogen exposures, for example, in ordinary diets and diet supplements (e.g., green tea) are rarely carried out.

8.2.2 Complexities of geographical/ cultural/ethnic factors It is well known that certain tumor types are more common in certain parts of the world and populations than others [62,63] (see Chapter 7). In the 1970s, it was widely assumed that all human populations are genetically the same with regard to spontaneous incidences of tumor types. On this assumption, the lowest rate of incidence for any tumor type anywhere in the world was taken as its “spontaneous rate” in all humans. Any excess incidence of a tumor type in a particular part of the world could then be considered due to some environmental influences. Overall, the excess was assessed 80%e90% of all tumors [64]. Certain observations supported this. Betel nut chewing leads to high incidences of carcinomas of the mouth in India and Southeast Asia [65]. Moreover, populations with low incidences of certain types of cancers were reported to show increases in incidences of cancers common in Western communities when those populations abandoned their indigenous cultures and adopted Western lifestyles [66] (Fig. 8.14). However, since then, there have been observations on the differences in incidences in tumors in ethnic groups which appear to share the same geography and culture. For example, African-American men suffer prostate cancer more frequently than European Americans [67]. As another example, the high incidence of nasopharyngeal carcinoma in Southern Chinese does not seem to be explained by viral (EpsteineBarr virus) and environmental factors alone [68]. The matter of the possible general role of different genetic makeups in different incidences of tumors in different ethnic/cultural populations groups has not been clarified.

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Human populaons aer migraon and / or alteraons in culture

Original human populaons

Culture-determined exposures to carcinogens*

Full / paral abandonment of original culture-determined exposures to carcinogens*

Full / paral adopon of new culture-determined exposures to carcinogens*

Loss of original geographydetermined exposures to environmental carcinogens*

Geography-determined exposures to carcinogens*

Geography-determined exposures to ‘new’ environmental carcinogens*

Potenal genec modifiers of suscepbility to carcinogens*

Potenal alteraon in incidences of potenal genec modifiers of suscepbility to carcinogens* due to intermarriage

Tumor formaon

Tumor formaon

* includes “modifiers” of primary carcinogens.

FIGURE 8.14

Some potentially complex aspects of the genetic, cultural, and geographical factors in tumor formation.

The most widely accepted view is that the different incidences of tumors in different parts of the world are probably due to largely unrecognized local environmental carcinogens, culturally determined exposures to carcinogens [69], and low-penetrance hereditary factors (Section 7.9).

8.2.3 Cross-sectional studies Cross-sectional studies measure the prevalence of conditions or characteristics of people in a population at a point in time or over a short period. Although they are essentially descriptive studies, their results can often suggest causative or risk factors associated with particular illness or behavior; for instance, the causal relationship between cataracts and vitamin status was originally investigated through a cross-sectional studyd The Blue Mountains Eye Study [70]. They may also be used to ascertain the prevalence of a

health-related behavior, such as the wearing of seat belts or participation in exercise. In crosssectional studies, it is not always necessary to investigate the whole population: a sample is usually sufficient, provided that the individuals in the sample are representative of the total group under consideration. Cross-sectional studies are useful in planning public health interventions. A population or group can be studied in a variety of ways: by questionnaire, by taking measurements (such as blood pressure), by analyzing blood specimens (e.g., for blood cholesterol levels), or by examining health care records [71]. While cross-sectional studies can provide information on things like the prevalence of a particular disease (how common it is), they cannot tell us anything about the cause of a disease or what the best treatment might be [72]. They are rarely used in studies of cancer causation or prevention.

8.3 Association does not prove causation

8.2.4 Cohort studies: finding changing incidences of disease These are generally prospective studies. The simplest kind of this study involves identifying particular subsets in a population and observing whether or not over time a particular disease occurs in the members of the subsets more frequently than in the general population [73]. For etiological factors, the studies always collect data on age, sex, occupation, and lifestyle (see in Chapter 7) (Fig. 8.15).

8.2.5 Case-controlled studies These are essentially retrospective studies. The principle involves comparing aspects of the occupations and lifestyles that individuals known to have a particular disease, to the same aspects of members of the general population who are known not to have the disease (see Ref. [73]). The method depends on accurate diagnoses of cases of the disease in question, paying attention to changes in terminology (see Chapter 10). Depending on various factors, terminological differences may cause patients to be inappropriately included or excluded from either or both the disease group and the control group. In studies of tumors which depend largely on histopathological diagnosis, it may be necessary to have the histopathological slides of all the cases revieweddeven by multiple pathologists. Case-controlled studies are cheaper, easier, and carried out more rapidly than prospective studies [74]. There is no need to establish actual incidence rates of the disease being studied.

8.2.6 Interventional studies In these, the observers intervene to create “test” and “control” groups. These are essentially controlled trials [75]. It is difficult to establish random or blinded allocations of individuals to each group in these studies (see in Appendix A9).

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8.3 Association does not prove causation 8.3.1 General In general, to identify a causative factor for a disease, the steps in the process followed are (i) To identify the associated factors and (ii) To investigate whether the association has causative significance or is spuriousdusually meaning the association is between two effects of a single cause. For example, in southern California, there may well be an association between melanomas of the skin and wearing flip-flops. The melanomas are not caused by the footwear. Both observations are associated with a lifestyle involving excessive exposure to the sun. Other associations might be explained by the multifactorial aspect of causation. Carrying boxes of matches in pockets may well be found to be associated with increased incidence of carcinoma of the lung [76]. However, this does not mean that the boxes of matches cause the carcinomas directly but may be explained by the necessary components in causation. The indirect bur primary causative factor of lung cancer may be seen to be the individual’s addiction to nicotine. It is the addiction which causes him/her to smoke cigarettes (direct but secondary cause). The carrying of boxes of matches (first observation) thus becomes associated with lung cancer (second observation) by way of being necessary to the secondary cause.

8.3.2 Bradford Hill’s guidelines The issue of noncausative associations has been recognized since the beginnings of epidemiology. The most widely quoted guidelines to establish causativeness of an association are those of Bradford Hill (1965) [77]. They were written in answer to the question “What aspects of that association should we especially consider before deciding that the most likely interpretation of it is causation?”

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Cohort studies Prospecve studies, (usually wait for cases to appear >10 years)

A

B

At the beginning of the trial, a subpopulaon is selected according to the hypothesis of the trial. If the hypothesis is that exposure to a certain agent is associated with the disease, then the subpopulaon is of individuals with known exposure to the agent. At this point, it is not known whether the incidence of the disease is different from the incidence in it the populaon as a whole.

At the end of the trial, the incidence of the disease in the subpopulaon in comparison with the whole populaon is determined. Hence the existence of an associaon is either shown or not shown.

Case-controlled studies Retrospecve studies, (cases are completed before the study is begun) A

C B

A

B

C

From the whole populaon, the subpopulaon of sufferers of the disease is idenfied.

At the same me, a “control” subpopulaon is taken from the whole populaon. The individuals in this subpopulaon have the same characteriscs (age, gender, occupaon, etc.) as individual members in the diseasesufferers group.

Idenficaon – by comparison with controls – of occupaonal, life-style or other factors (colored dots) which might have been responsible for the disease in the sufferers.

FIGURE 8.15 Cohort and case-controlled studies.

The guidelines were based on consideration of data according to their (i) (ii) (iii) (iv)

“Strength,” Consistency, Specificity, Temporality,

(v) Appropriateness of biological gradient (i.e., doseeincidence relationship), (vi) Plausibility, (vii) Coherence, (viii) Consistency with experimental data, and (ix) Consistency with analogous data.

8.4 Other aspects of interpreting cancer-causation epidemiological data

The guidelines have been discussed by several authors, some of whom suggest changes in detail [78e81]. However, Hill’s comments on the value of his guidelines remain valid: What I do not believedand this has been suggesteddthat we can usefully lay down some hard-and-fast rules of evidence that must be obeyed before we can accept cause and effect. None of my nine viewpoints can bring indisputable evidence for or against the cause-and-effect hypothesis and none can be required as a sine qua non. What they can do, with greater or less strength, is to help us to make up our minds on the fundamental questiondis there any other way of explaining the set of facts before us, is there any other answer equally, or more, likely than cause and effect? (see Ref. [77]).

8.4 Other aspects of interpreting cancercausation epidemiological data 8.4.1 Importance of finding factors least associated with others In many studies of possible causes of cancer in whole populations, problems arise due to multiple features being associated with the type of tumor in question. In the example above of melanomas in southern California, the following features might be found to be associated with a higher incidence of the disease: bleached hair, ownership of a surfboard, roof racks on personal motor vehicle, wearing long-legged swimwear, etc. All of these features would be strongly associated with each other as well as with melanoma. They might then be called “highly interassociated” features associated with melanoma. However, in a study, a question might relate to use of sunscreens lotions (see Section 8.1). Low use of sunscreens would be associated with melanoma, but not with any of the other associated factors. Low use of sunscreen agents is then called a “lowly interassociated” feature, from which a causative relationship between UV exposure and melanoma can be inferred.

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N. b. The terminology of “dependent” and “independent” variables has been avoided here. The terms “closely associated” and “little associated” are considered more precise. Statistical methods for evaluating associations have been described in International Agency for Research on Cancer (IARC) publications [82,83].

8.4.2 Use of “risk” for associations In general usage, a “risk” is, or is the likelihood of, a prospective unwanted event which can be avoided in some way. Thus, “a risk of driving a car fast is an accident”; “the risk of driving a car fast is high.” “Risk” is not normally applied to something which is unavoidable and inevitable. Hence, a phase such as “the risk of growing old” is usually meant comically. However, many authorities do not accommodate how the general population uses the terms. For example, the US National Cancer Institute defines a “risk factor” as Something that increases the chance of developing a disease. Some examples of risk factors for cancer are age, a family history of certain cancers, use of tobacco products, being exposed to radiation or certain chemicals, infection with certain viruses or bacteria, and certain genetic changes [84].

The inclusion here of “age” is arguable because it is inevitable, and although associated with increased cancer incidence, it is not of itself an avoidable cause of cancer. Under “Risk Factors for Cancer,” the website states Although some of these risk factors (in a list following) can be avoided, othersdsuch as growing olderdcannot. Limiting your exposure to avoidable risk factors may lower your risk of developing certain cancers.

The list is “Age, Alcohol, Cancer-Causing Substances, Chronic Inflammation, Diet, Hormones, Immunosuppression, Infectious Agents, Obesity, Radiation, Sunlight, Tobacco.”

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Cancer.net, the website of the American Society of Clinical Oncology (ASCO), states A cancer risk factor is anything that increases a person’s chance of getting cancer. Yet most risk factors do not directly cause cancer. Some people with several risk factors never develop cancer. And others with no known risk factors do [85].

These definitions include both factors with proven roles in causation and factors with no known role in causation. This usage of “risk” in this way might be thought of as unfortunate because of its possible effect of creating unjustified alarm in the population (see also in Chapter 7). On the other hand, it may persuade more middle-aged individuals to participate in screening programs, so that their old age can be longer and more enjoyable than otherwise.

8.4.3 Classification of “risk”/association: absolute risk, difference in absolute risk, relative risk, and odds ratio Because in the literature the influences of possible carcinogens are often discussed in terms of “risk,” it is important to note that risk is used in epidemiology in three different contexts. These can be illustrated by considering a hypothetical population of 40-year-old individuals and their risk of developing a particular type of cancer in the next 30 years. (a) Absolute risk This is defined as the actual incidence of a given disease in a given population over a given period of time. It is the same as “absolute incidence” (see Section 7.2.1). To continue with the hypothetical population of 40-year olds, the absolute incidence/risk of developing a particular cancer in the next three decades of their lives might be found to be 5.25%.

(b) Difference in absolute risk If, say, a group of 40-year-old persons were divided into consumers and nonconsumers of a particular dietary additive, in the study, it might be found that the consumers of the additive have an incidence of the tumor of 5.5% and the nonconsumers of the additive an incidence of 5.0%. In this situation, the difference in absolute risk of consumption of additive versus nonconsumption of additive for the particular cancer is 0.5%. (c) Relative risk Relative risk is the increase in incidence rate of a disease in a test group as a percentage of the incidence rate in the control group. In the group of 40-year-old persons, the relative risk of additive consumption for development of the particular cancer is 0.5 O 5.0
100 ¼ 10%. (d) Odds ratio This is the ratio between the risk/incidence of an event in the presence of an exposure and the risk/incidence in the absence of the exposure. Odds ratio ¼ ðNumber of new casesÞ= ðnumber in whole population  number of new casesÞ In the population of 40-year-old persons, the odds ratio is 5.5:5.0 ¼ 1.1:1.0.

8.4.4 Attribution of fractions of “risk” In studies of incidences of tumors which can be due to multiple factors, attempts are made to apportion the “total risk” among these factors. A common method is to use Cox proportional hazards models, which essentially are based on degrees of covariation (see independence of variables) [86].

8.5 Problematic issues with low-level or disputed carcinogens and carcinogenic factors

8.5 Problematic issues with low-level or disputed carcinogens and carcinogenic factors Here, a “carcinogen” refers to physical or chemical agents such as X-rays or methylcholanthrene, and “carcinogenic factor” to physically or chemically undefined agents or activities, for example, air pollutant, where the composition of the pollution is unknown, or alcohol abuse, where the mechanism of action is unclear (see below). Since the 1970s, an enormous number of chemicals and other factors have been investigated in great detail for possible carcinogenic potency, with controversies concerning many agents. The IARC maintains the longest list, in five categories (1, 2A, 2B, 3, and 4) in descending order of positive evidence. The American Conference of Governmental Industrial Hygienists (ACGIH) has a 5-category system which differs from the IARC categories in some details. The classification of the European Union has only three categories. The US National Toxicology Program divides carcinogens into two groups. Many chemicals do not appear on all lists. This does not necessarily indicate a controversy, but rather that one agency may not have completed an evaluation of the particular substance [87]. The following is only a small sample of the problematic issues.

8.5.1 Aging and background radiation enhancing “normal” rates of mutation Aging has long been an accepted risk factor for most of the common types of tumors [88,89]. This is based on increases in incidence of malignancies with age which have now been documented for over half a century (Chapter 7, Table 7.1). In relation to external radiations causing numerous kinds of cancers, then those living in high natural radiation sites (e.g., on granite) would be expected to have more cancers, and occurring at younger ages, than those living in sandy areas. This has been suggested to be the

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case in regions, for example, in Arizona in the United States [90] and Scotland in the United Kingdom [91], where radon accumulates in the cellars and low-lying parts of houses, but conclusive data are not available. In principle, increasing age could contribute to tumor formation by several possible mechanisms as follows: (i) All cells which turnover (labile cells, see Appendix A1.3.2) may accumulate genomic errors due to inherent defects in replicative fidelity of DNA or inescapable internal radioactivity (see in Section 3.1.1). (ii) Many humans have hereditary predispositions which only manifest late in life. Individuals, and also ethnic groups, could vary in their “normal” DNA error rates. Thus, in hereditary nonpolyposis colorectal carcinoma, the tumors occur approximately two decades earlier than in individuals without the syndrome. It is possible that other hereditary predispositions exist which manifest only in the eighth or higher decades in life. The identification of these would be difficult because many of the family members may have died of one or more other causes before the age of predisposition is reached. (iii) Exposure to a carcinogen, or withdrawal of a carcinogen-inhibitor, may occur only in later ages, in relation to lifestyle or other changes in the individual.

8.5.2 Air pollution “Indoor” air pollutants include radon, which accumulates in cellars of houses in granitebased areas (see above), asbestos used in construction of houses, passive smoking, and perhaps some products of cooking [92]. “External” air pollutants are mainly combustion products of all forms of fossil fuels used in electricity generation, home heating, internal

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combustion engines, and other applications of fossil energy.

8.5.3 Lung cancer in never-smokers This category is difficult to separate from the passive cigarette smokeeexposed group. The lung cancers in both groups tend to be mainly adenocarcinomas, while those in active smokers are more commonly squamous cell type. The causes of lung cancers in never-smoked actively or passively are thought to be the various air pollutants mentioned above [93,94].

8.5.4 Water pollution, chlorination Waste products of many chemical and metallurgical industries, as well as cleaning agents used in workshops and other machinery facilities, can enter the water supplies. Chlorination can act on some organic matter in natural water supplies to produce chemicals which are genotoxic in laboratory tests. Use of nitrogen fertilizers in agriculture has been proposed to have similar possible effects. Toxins from cyanobacteria in the water supplies may contribute to higher incidences of liver cancer in some Asian countries [95].

on Asbestos [101] found for stomach cancer a combined RR of 1.17 (95% CI 1.07e1.76) for cohort studies and an RR of 1.11 (95% CI 0.76, 1.64) for case-control studies. For colorectal cancer, an RR of 1.15 (95% CI 1.02, 1.31) for cohort studies and an RR of 1.16 (95% CI 0.90, 1.49) for case-control studies were reported. (c) Particular properties of chrysotile asbestos Serpentine asbestos (chrysotile) has different properties and biological effects from the amphibole kinds of asbestos and is said to pose not health risks [102,103]. Serpentine fibers are seen in autopsies, but their numbers do not correlate with pleural plaques [104], and a recent publication suggests that they are dissolved in lung tissue macrophages in 3e 6 months, rather than 50 þ years for amphibole fibers [105]. Another study in human autopsy material suggests that chrysotile may be more persistent than months in human lungs [106]. Much of the difficulty in studies is that in commercial products, the different kinds of asbestos may be mixed. The pathogenicity of chrysotile has been, and remains, hotly debated [107,108].

8.5.6 Affected family members 8.5.5 Low dose exposure to chrysotile and bronchogenic lung cancer (a) Pulmonary and mesothelial tumors As mentioned in Chapter 3, amphibole kinds of asbestos (especially crocidolite) cause bronchogenic carcinoma, as well as malignant mesothelioma [96] and malignant pleural mesothelioma [97,98]. (b) Other cancers There have been a large number of studies reporting on associations between asbestos exposure and stomach and other gastrointestinal tract cancers [99,100]. The risk estimates for both stomach and colorectal cancers vary but are generally modest. A review of the US Committee

The high penetrance hereditary factors seem to apply to only a small number of tumor types, while the possibility contributions of lowpenetrance genomic events and multiple events have not been fully assessed.

8.5.7 Alcohol consumption Ethanol consumption has been shown to be associated with liver cancer, but for other tumors, a direct causative relationship is unclear. No association has been shown for head and neck cancers [109]. Similarly, with gastric cancer, a role has been proposed. However, for the last 50 years, alcohol consumption has been rising in Western

8.5 Problematic issues with low-level or disputed carcinogens and carcinogenic factors

countries, where the incidence of gastric cancer has been falling [110] (Fig. 8.16). Of itself, ethanol is a coagulant of all macromolecules and is not genopathic [111,112]. Its metabolic product (acetaldehyde) is a Group 1 carcinogen (IARC) and is produced in the liver. Hence, a biologically feasible causative mechanism exists for ethanol and liver tumors. It is not metabolized by esophageal cells, so no chemical mechanism is evident for the (disputed) association (see above). In addition, neither ethanol nor acetaldehyde access the colon, where increased cancer rates are documented. The topic has been recently reviewed concluding that “The conclusive biological effects of alcohol on tumor progression and malignancy have not been investigated extensively using an animal model that mimics the human disease” [113]. To explain the association, it may be remembered that alcohol is consumed in complex mixtures, such as beer, wines, and spirits, which contain additional carcinogens. The putative additional carcinogens might act on the colon, creating the association with ethanol consumption indirectly.

The History Of Alcohol Consumpon In America

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8.5.8 Caffeine, especially in coffee The possibility of carcinogenic potency of caffeine was mooted as early as 1968, when it was shown to produce chromosomal aberrations in cells in vitro [114]. Some epidemiological studies in the 1980s suggested that coffee drinking is associated with carcinoma of the pancreas [115]. Other studies supported [116,117] or did not confirm the association [118]. A recent prospective study found “In a prospective study of coffee intake with the largest number of pancreatic cancer cases to date, we did not observe an association between total, caffeinated, or decaffeinated coffee intake and pancreatic cancer” [119].

8.5.9 Pharmaceuticals, other healthrelated products, talc Several cytotoxic drugs used to treat cancer may cause tumors and hence “second malignancies” in cancer patients (see in Chapters 15e17). The most clearly established is etoposide causing leukemia. Certain nonprescription agents such cholesterol-lowering agents have been associated with increased cancer risk [120,121]. Recently, talc, as talcum powder, has been claimed, due to contamination by asbestos, to have caused internal malignancies. How talc or asbestos might access the relevant parent kind of cell (see in Section 3.1.2) to make this assertion biologically feasible is unclear. Recently, widely used angiotensin-converting enzyme inhibitors have been linked to increased risk of lung cancer [122]. Some aspects of the study have been criticized [123].

8.5.10 Glyphosate KEY

All Beverages

Spirits

Wine

Beer

FIGURE 8.16 The history of alcohol consumption in the United States. Source: VinePair. https://vinepair.com/articles/ americas-consumption-beer-wine-spirits-since/ (Data comes from the National Institute on Alcohol Abuse and Alcoholism.)

The herbicidal qualities of glyphosate [N(phosphonomethyl)glycine] were discovered in 1970 and has been sold since 1974 under various names, including “Round-up.” The substance blocks a metabolic pathway which occurs only

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in plants. No evidence of toxicity to animals or humans was published until 1999, when a study was reported to have shown an increased incidence of non-Hodgkin’s lymphoma in agricultural workers using this herbicide [124]. Reviewing the subject Greim et al. concluded The lack of a plausible mechanism, along with published epidemiology studies, which fail to demonstrate clear, statistically significant, unbiased and non-confounded associations between glyphosate and cancer of any single etiology, and a compelling weight of evidence, support the conclusion that glyphosate does not present concern with respect to carcinogenic potential in humans [125].

Nevertheless, in March 2015, the IARC concluded that glyphosate is a probable carcinogen [126]. This assessment has not been supported by assessments by an EU agency or the WHO/ FAO. The US government Agriculture Health Study publication on the topic concluded In this large, prospective cohort study, no association was apparent between glyphosate and any solid tumors or lymphoid malignancies overall, including NHL and its subtypes. There was some evidence of increased risk of AML among the highest exposed group that requires confirmation [127].

The Environmental Protection Agency final report is not available at the time of writing. Additional references for and against the IARC finding are available (see Refs. [128] and [129]).

8.5.11 Red meat Cooked, especially grilled meat, has been considered a source of possible human carcinogens since the 1980s, on the basis of Ames test results (see Section 8.6 below) on extracts of many kinds of foods [130]. In 1990, Willet and coworkers published a large prospective trial of fat intake and this disease, in which red meat in the diet was implicated [131]. Of interest is that the study

reported “A low intake of fiber from fruits appeared to contribute to the risk of colon cancer, but this relation was not statistically independent of meat intake.” By 2014, many studies had been reported to show that there are several potential biochemical mechanisms relating red meat to cancer, including heterocyclic amines, polycyclic aromatic hydrocarbons, N-nitroso compounds, and heme iron [132]. In October 2015, the IARC issued a press release on the results of the evaluation of the carcinogenicity of red and processed meat, concluding that red meat is “probably carcinogenic to humans” and processed meat is “carcinogenic to humans” [133]. From October 2015 to May 2018, approximately 70 reviews are listed in PubMed search “red meat cancer” to go with the more than 200 reviews published before that. A critical analysis of the laboratory test evidence for red meat causing cancer is available [134].

8.5.12 “Poor diet” and “fiber” Diet, in one way or another, has been blamed for cancer for many centuries [135]. Most early studies focused on known or suspected carcinogens, e.g., arsenic and nitrosamines, taken orally in food [136]. Much attention is now given to the relative composition of the major dietary components by chemical: carbohydrate, protein, fat, and undigestible fiber. The topic is complex for reasons of terminology as well as food chemistry. (a) Definition of “poor diet” “Poor diet” is a vague term in relation to both epidemiological and experimental studies. It was originally used for diets with specific deficienciesd for example, in protein (causing marasmus in children), vitamins, or simply calories. More recently, “poor diet” has been used to describe high-fat, high-carbohydrate, and lowfiber “Western” diets.

8.5 Problematic issues with low-level or disputed carcinogens and carcinogenic factors

(b) Diets with a low component of vegetable fiber (cellulose) and prevention of carcinomas of the colon and rectum “Fiber” in this context initially referred to fibrous indigestible vegetable material in the diet, but more recently, the definition has been expanded to include all indigestible vegetable material. The possibility that dietary fiber might prevent colorectal cancer was proposed by Burkitt in 1971 based on the different incidences of the disease in African and European populations in Uganda [137]. Large numbers of studies have been conducted, but conclusive results appear to have been made difficult by measurement errors and possible concurrent confounding influences, such as folate consumption [138]. Suggested mechanisms of the effect have included reduced transit times of feces in the colon, adsorption of carcinogens by the fiber, and reduction of the bacteria in the colon which convert noncarcinogens (such as bile acids) to carcinogens. It is generally accepted that a low fiber diet must be a lifelong condition for predisposition to these tumors because there is little evidence that a switch from low-fiber to high-fiber diet as an adult has any preventative effect [139].

8.5.13 The World Cancer Research Fund/American Institute for Cancer Research studies (a) Diet The first report on this topic was published in 1997 [140]. The Second Expert Report was published in 2007, with Guidelines introduced the following paragraph: Since the early 1980s, relevant United Nations agencies, national governments, authoritative nongovernmental organisations, and researchers and other experts in the field have agreed that food and nutrition, physical activity, and body composition

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are individually and collectively important modifiers of the risk of cancer, and taken together may be at least as important as tobacco. By the mid-1990s the general consensus became more solidly based on methodical assessment of the totality of the relevant literature. Thus: ‘It is now established that cancer is principally caused by environmental factors, of which the most important are tobacco; diet and factors related to diet, including body mass and physical activity; and exposures in the workplace and elsewhere.’ This statement introduces the recommendations made in the first WCRF/AICR report [141].

After this, the Continuous Update Project collated new data and the results were quantitatively summarized in metaanalyses [142]. The support in the 1997 document for the opinion that fruits and vegetables play a role on cancer etiology was withdrawn, but the opinion on the etiological role of lack of fiber in colorectal cancer was upgraded from “probable” to “convincing.” The Abstract of the article was as follows: The World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) current dietary recommendations for cancer prevention include “eating at least five portions/servings of a variety of non-starchy vegetables and or fruits every day”. The most recent report coordinated by WCRF/AICR (2007) concluded that the evidence of a protective effect of fruits and vegetables on cancer was either “probable”-mouth, pharynx and larynx, oesophagus stomach, lung- or “limited suggestive”-nasopharynx, lung, colorectum, ovary, endometrium, pancreas, liver-. In a previous report published by WCRF/ AICR in 1997, the evidence of the association of fruits and vegetables with cancer risk was considered convincing. This judgement was based mainly on the results of case-control studies. The association of fruit and vegetable intake and the risk of colorectal, breast and pancreatic cancer was re-examined in the Continuous Update Project (CUP) and the results were quantitatively summarised in meta-analyses. The CUP, with more data available, has confirmed the conclusion of the WCRF/AICR second expert report that there is no convincing evidence that fruits and vegetables play a role on cancer aetiology. On the other hand, evidence that is more consistent has been collected in the CUP about the role of dietary fibre and colorectal cancer. The evidence on the role of dietary fibre in

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colorectal cancer aetiology has been recently upgraded by the CUP expert panel from probable to convincing.

The Third Expert Report of this project into Diet, Nutrition, Physical Activity, and Cancer published in 2018 supports associations between diet and cancers [143]. The “risk”/factors for which associations are sought are classified as follows: Whole grains, vegetables, and fruit; meat, fish, and dairy; preservation and processing of foods; nonalcoholic drinks; alcoholic drinks; other dietary exposures; (lack of) physical activity; body fatness and weight gain; height and birthweight; lactation. Data are collected for the following cancer types: bladder, breast, breast cancer survivors, cervical, colorectal, endometrial, gallbladder, kidney, liver, lung, mouth, pharynx, larynx, nasopharyngeal, esophageal, ovarian, pancreatic, prostate, skin, and stomach. The recommendations are as follows: be a healthy weight; be physically active; eat whole grains, vegetables, fruit, beans; limit “fast foods”; limit red and processed meat; limit sugary drinks; limit alcohol; do not rely on supplements, and breastfeed your baby. In recent years, there have been numerous papers addressing the issues of whether or not compliance is associated with a fall in mortality in all cancer types or particular cancer type. For example, Vergnaud AC, Romaguera D, and Peeters PH et al. reported on a study which included 378,864 participants from nine European countries with mean follow-up of 12.8 years [144]. There were 23,828 deaths identified. Participants within the highest category of the WCRF/AICR score (five to six points in men; six to seven points in women) had a 34%

lower hazard of death (95% CI: 0.59, 0.75) compared with participants within the lowest category of the WCRF/AICR score (0e2 points in men; 0e3 points in women). Similar findings were described in a metaanalysis conducted by Jankovic N, Geelen A, and Winkels RM et al. in 2017 [145,146]. These studies are of older adults. Whether or not the data accurately reflected lifetime diet or diet at the time of the questionnaire is difficult to establish. Smoking histories were little mentioned. (b) Lack of physical exercise There is no known direct chemical basis for this. Exercise increases metabolism of energyproducing dietary factors, especially carbohydrates and triglycerides, but a far as is known does not qualitatively induce any biochemical event. Lack of physical exercise may be associated with certain dietary habits or ill-health due to some other factor or process, which may have carcinogenic potency. (c) Obesity Calories in dietary carbohydrates, triglycerides, and amino acids alone are not carcinogenic. A possible suggestion must be that to become obese, lack of exercise and excess calorie intake is necessary [147,148]. In individuals, obesity per se may not be a causative factor. For example, the causative factor may be in the food eaten but may only have its effect if eaten in the high doses associated with eating the excess calories necessary to become obese. The food which is excessively ingested may contain an incidental excess of carcinogensdor excess inhibitors of inhibitors of naturally occurring carcinogensdwhich cause the tumors. Without knowing what the carcinogens are, the value of losing weight by calorie restriction cannot be estimated. In fact, the individual may cease eating calorific foods which do not contain a carcinogen and increase the intake of the food which does.

8.6 Laboratory methods in the identification of environmental carcinogens

8.5.14 Gut flora There is a substantial literature on gut flora and carcinogenesis, beginning with the suggestion that not-otherwise-pathogenetic microorganisms in the bowel, essentially the large bowel, might produce carcinogens which cause cancer in the immediately epithelium (i.e., colonic epithelial cells) [149e152]. More recently, it has been proposed that colonic microorganisms might produce carcinogens which pass to the bloodstream and cause cancers elsewhere in the body [153]. The authors suggest that “Functional contributions of the gut microbiota that may influence cancer susceptibility in the broad sense include (i) harvesting otherwise inaccessible nutrients and/or sources of energy from the diet (i.e., fermentation of dietary fibers and resistant starch); (ii) metabolism of xenobiotics, both potentially beneficial or detrimental (i.e., dietary constituents, drugs, carcinogens, etc.); (iii) renewal of gut epithelial cells and maintenance of mucosal integrity; and (iv) affecting immune system development and activity. Understanding the complex and dynamic interplay between the gut microbiome, host immune system, and dietary exposures may help elucidate mechanisms for carcinogenesis and guide future cancer prevention and treatment strategies.” Some animal experiments have been reported [154] but given the shortness of the experiments of laboratory animals as well as metabolic differences, the relevance of the outcomes of such work to human cancers is unclear.

8.5.15 Acrylonitrile Acrylonitrile is a colorless, volatile liquid with a pungent, onion-like odor. Acrylonitrile is widely used in industry to produce rubber, resins, plastics, elastomers, and synthetic fibers and to manufacture carbon fibers used in aircraft, defense, and aerospace industries. It is

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not only carcinogenic in rats but no carcinogenic effect in humans has been confirmed [155].

8.5.16 Wood dust Exposure to wood dust has been reported in several studies as a cause of nasopharyngeal cancer [156] but a multicenter case-control US study found only a modest association with wood dust that was explained by confounding by a stronger association with formaldehyde [157].

8.6 Laboratory methods in the identification of environmental carcinogens 8.6.1 Background Laboratory tests are relied on in the determination of whether or not particular chemicals, either in the environment or newly developed by the chemical and pharmaceutical industries, may be carcinogenic in humans. During more than a century of research, hundreds of different tests have been developed. These have used mainly whole animals, eukaryote cells in culture, and bacteria (Table 14.2). They are key factors in the classifications of chemicals by the IARC and other agencies (see Section 8.1.3). The following three subsections outline the principles of some of the laboratory tests. Other uses of laboratory animal experiments are indicated in Fig. 8.17. The ways in which these tests are currently used by regulatory authorities is discussed in Section 8.2.5.

8.6.2 Tumors in animals Historically, these were the first kinds of test for carcinogenic potency. Successful models began with the discovery of the rabbit and rodent skin model for carcinogens. These models closely mimic the skin cancers associated with exposures of the skin of workers to chimney soot or mineral oils (see Section 8.1.1, above).

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8. Prevention of tumors

(A)

(D)

(B)

(E)

(C)

(F)

FIGURE 8.17 Microimages of tumors caused by benzo[a]pyrene in mice. (A -C) Histological appearance of a fibrosarcoma (A), a rhabdomyosarcoma (B), and a squamous cell carcinoma (C) induced in AhR(þ/þ) male mice by subcutaneous injection of B[a]P. (Hematoxylin/eosin staining,
100.) (D -F) Histological appearance of a squamous cell carcinoma (D), papilloma (E), and keratoacanthoma (F) induced in AhR(þ/þ) female mice by topical application of B[a]P. (Hematoxylin/eosin staining,
100 for D,
5 for E and F.) Source: Shimizu Y, Nakatsuru Y, Ichinose M, et al. Benzo[a] pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A 2000;97(2):779 -82. https://doi.org/10.1073/pnas.97.2.779 reproduced with permission.

Laboratory animals have been used in these tests according to the native susceptibility of the particular species and strain. Smaller animals are preferred to larger ones because of the costs of maintaining them for long periods (usually 2 years or more) [158e160]. Certain carcinogens cause tumors in a variety of kinds of parent cells [161], while other agents cause tumors in only a few kinds of parent cells (See Fig. 8.17).

Outbred animals are rarely used. Longestablished strains such as BALB/c mice and SpragueeDawley rats are widely used in many areas of research. However, there are differences in the susceptibilities of different strains of almost all laboratory animals to tumors. The reasons for the inconclusive results in animals may lie in different defenses against carcinogens in the different species. Factors in the care,

8.6 Laboratory methods in the identification of environmental carcinogens

diet, and housing of the animals may influence results [162,163]. Mice have been genetically engineered in various ways for specific research uses [164]. The “engineering” includes the following: (i) Transfers of known oncogene/growth factor genes, usually inserted to be under control of the promoter of a tissue-specific gene (“oncomice”). Tumors arising in advanced genetically engineered mouse models (GEMMs) closely mimic the histopathological and molecular features of their human counterparts, display genetic heterogeneity, and are able to spontaneously progress toward metastatic disease. As such, GEMMs are generally superior to cancer cell inoculation models, which show no or limited heterogeneity and are often metastatic from the start. Given that GEMMs capture both tumor cell-intrinsic and cell-extrinsic factors that drive de novo tumor initiation and progression toward metastatic disease, these models are indispensable for preclinical research. [165]. (ii) Knock out the function mutations in known tumor suppressor genes [166]. (iii) Chimeric mice: These are created from embryonic stem cells (ESCs) of genetically engineered mouse models (GEMM-ESCA). The technique allows rapid introduction of additional genetic modifications and subsequent production of chimeric mice from ESCs derived from existing GEMMs [167]. (iv) “Humanized” mice (HM): These strains of mice almost completely lack innate immune systems and can be engrafted with human immunocompetent cells at early stages so that graft-versus-host reactions do not occur in the mice. HM models have become feasible as a result of the identification of increasingly immunocompromised strains of mice into which a human immune system could be successfully engrafted [168].

237

The simpler rodent assays remain an important test in the “batteries” of tests recommended by regulatory authorities (see Section 8.2.5), but the genetically engineered animals are probably too expensive for wide routine use.

8.6.3 Enhanced rates of malignant transformation in cells cultured in vitro Many agents including radiations and chemicals of many different classes are able to cause enhanced rates of malignant transformation in vitro (see Section 2.4.6) [169e171]. The backgrounddin spontaneous transformation in vitro and virally caused transformationdto these tests is given in Sections 2.4.6 and 4.1.3. Here, the aspects of the phenomenon which affects its usefulness as a test are mentioned [172,173] (Fig. 8.18). (a) Methodological issues (i) Transformation in vitro is much more common per number of growing cells than tumor formation in vivo. (ii) It occurs in only a very small proportion of cultured cells (i.e., before the culture becomes “senescent”). (iii) The rate of chemically induced, nonviral transformation varies according to the kind of cell being grown, and the culture medium used [169]. A recent review has found that a Syrian hamster cell line and the BALBc 3T3 cell lines were more reliable than a C3H10T1/2 line as tests of potential carcinogenicity in humans [174]. However, the same cell line has shown that lead acetate is capable of transforming these cells, while not being an established carcinogen in humans [175]. (iv) Many kinds of cells, especially epithelial cells, cannot be cultured in vitro for sufficient periods of time and so cannot be used for these tests. Because of this, the testing methods usually involve fibroblasts. However, fibroblasts are biologically quite different to other cells (see Appendix

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8. Prevention of tumors

Transformation in vitro. Neoplastic transformation of HELF cells exposed to 0.0, 0.5, 1.0, or 2.0 mM arsenite (As) for about 15 weeks (30 passages). C, control (untreated) HELF cells. A549 carcinoma cells served as the positive control. Morphological images of cells (A) after culture with 10% FBS (bars ¼ 500 mm) and (B) after culture with 1% FBS (bars ¼ 50 mm). (C) Photomicrographs of cell colonies in soft agar; bars ¼ 500 mm. (D) The number (mean  SD) of cell colonies in soft agar (n ¼ 3). (E) Representative pathological sections of tumors 4 weeks after cells were inoculated into nude/BALB/c mice; tumors induced by arsenite-transformed cells consisted of undifferentiated and spindle cells (bars ¼ 100 mm). (F) Volume (mean  SD) of tumors in nude/BALB/c mice (n ¼ 6). *p < 0.01 compared with control group. **p < 0.05 compared with 0.5 or 2.0 mM arsenite groups. #p < 0.05 compared with mice implanted with cells exposed to 0.5 mM arsenite. Source: Li Y, Xu Y, Ling M, et al. mot-2eMediated cross talk between nuclear factor-kB and p53 is involved in arsenite induced tumorigenesis of human embryo lung fibroblast cells. Environ Health Perspect 2010;118:936e42., reproduced with permission from Environmental Health Perspectives.

FIGURE 8.18

8.6 Laboratory methods in the identification of environmental carcinogens

A1.1.4), and because carcinogens act only on specific kinds of parent kind of cells (see Section 3.3.6), fibroblasts may be an inappropriate model. (b) Advantages (i) The tests are far cheaper than whole animal tests and so can be done in large numbers (the xxx protocol recommends testing putative carcinogens in 60 cell lines). (ii) Multifactoriality can be tested in this model. For example, pretreatment of cell cultures with one type of agent followed by another can increase the rate of transformation with subsequently administered other agents, for example, radiations [176] followed by chemicals. The general view has been that transformation in vivo is a valuable, but not perfect, indicator of carcinogenicity in humans [177,178].

8.6.4 Other genopathic phenomena used for testing potential carcinogenicity The main genopathic effects and phenomena are described in Appendix A3.1.2 and Appendix A7.2. This subsection describes the principles of particular tests. The rationale for these tests includes the assumption that if an agent has one or more of these effects in experimental systems, it may also have carcinogenic effects in humans. (a) In living animals Whole animals are also used for testing potencies of agents for inducing nuclear structural abnormalities, chromosomal aberrations, developmental defects, and germline mutations. All of these changes may be used as the surrogate event for the beginning of tumor formation [171,179,180]. A commonly recommended assay for nuclear structural abnormalities is the mammalian erythrocyte micronucleus test (OECD Test 474) [181]. Another is the mammalian bone marrow chromosomal aberration test (OECD Test 475) [182,183].

239

Assays of these kinds are part of the battery of tests for pharmaceuticals recommended by the Food and Drug Administration (FDA) [180]. Examples based on damage appearing during development include embryonic lethality and the appearance of bodily deformities (teratogenesis) in offspring of exposed parent animals. This has been suggested to imply a genomic event caused in the embryonic or fetal cells of the developing offspring [184]. Other tests involve germline genomic events in rodents, Drosophila, or zebra fish [185]. Valid cross-species inferences from these tests may be difficult [186]. (b) In cultured cells In addition to transformation in vitro (see previous subsection), the following tests can be used. (i) In vitro mammalian cell micronucleus test

This test is recommended in the FDA guidelines (see Ref. [180]). The cells are exposed to the test agent and then examined for small nuclei, indicating disturbance in the mitotic process, especially in the distribution of chromosomes to daughter cells. A large number of kinds of cells can be used, including human peripheral blood lymphocytes (OECD TG487) [187]. (ii) In vitro mammalian chromosome aberration test

For this test (OECD Test No. 473) [188], a variety of sources of cells, including primary explants, for example, of peripheral blood leukocytes [189], or of human or mammalian cell lines, can be used. Methods for visualizing aberrations are also various (see Chapter 5) (Fig. 8.19). (iii) In vitro mammalian cell gene mutation assay

A widely used example of this kind of test is the mouse lymphoma assay/thymidine kinas locus assay (OECD Test 476) [190,191]. The cells in the assay are heterozygous for a gene which encodes an enzyme which is capable of incorporating analogues of thymidine into DNA. The test cells are killed when they divide in the presence of a toxic analogue of thymidine (trifluorothymidine) (see Refs. [190,191]). In the

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8. Prevention of tumors

In wild-type, or specific strains of whole animals

In genecally engineered whole animals, e.g. Big Blue® and Mutamouse®

Direct carcinogenicity

Test No. 474: Mammalian Erythrocyte Micronucleus Test

Damage to gametogenesis, or embryonic development, including lethalies In vivo Mammalian Chromosome Aberraon Test

Germ-line mutaon

Damage to DNA: Breaks Unscheduled DNA synthesis (‘UDS’)

Somac mutaon

In cultured eukaryoc cells

In vitro micronucleus (MN)

Cells can by primary explants (e.g. blood lymphocytes), or human or animal cell lines

In vitro chromosomal aberraons test

Somac mutaon e.g. mouse lymphoma assay / thymidine kinase locus assay. Damage to DNA: Comet test Extracted DNA

In bacteria Mutagenesis, e.g. Ames Test® Salmonella with genecally suppressed (but not deleted) gene for hisdine synthesis + microsomal enzymes for acvang exogenous chemicals. (The carcinogen has no effect without the acvang enzymes.

Add putave carcinogen

Some bacteria grow without hisdine, indicang a de-repressing mutaon of the hisdine synthesis gene.

Other tests on bacteria are mainly damage to DNA: Breaks, unscheduled DNA synthesis (‘UDS’), adducts

FIGURE 8.19

Some commonly used genopathic assays in testing for potential carcinogenicity in humans.

presence of a mutagen, the only cells which survive are those which have undergone a loss-offunction mutation in the second allele of the gene. (c) Tests in bacteria In these methods, the carcinogenesissurrogate genopathic phenomenon is usually a genomic event resulting in a phenotypic change (Ames test) [192,193]. This test in bacteria is widely used as an indicator of potential carcinogenicity in humans. The basis of the test is as follows. Strains of Salmonella are used which have genetically suppressed (but not deleted) gene for histidine

synthesis. Histidine is essential for growth of these bacteria. One sample of the bacteria is then mixed with the chemical being tested, and also microsomal enzymes (often rat liver homogenates). These enzymes are necessary for activating exogenous chemicals (see Section 4.4.1). Another sample of bacteria are mixed with the microsomal enzymes, but not the test chemical. The samples are then grown separately on media without histidine. Any cells which grow normally have undergone a derepressing mutation of the histidine synthesis gene. A higher

241

8.6 Laboratory methods in the identification of environmental carcinogens

number of growing cells from the sample containing the test substance compared with the number from the sample without the substance indicate that more of the derepressing mutations occurred in association with the test chemical, i.e., the test chemical is a mutagen. The dependency on activation by the liver homogenates raises the issue that such activation may not be appropriate for some chemicals and routes of exposure to carcinogens in humans. Numerous modifications are described [194]. The test is widely considered the best available for many kinds of chemicals [195,196]. Tests of this general nature are recommended in the FDA guidelines [197]. (d) Other tests A variety of other tests are used in general genotoxicity (genopathicity, see Section 4.1.1) testing and are not commonly applied to carcinogenesis (see Table 8.1 and ref [179]). The tests include those for DNA damage, such as the comet assay (for strand breaks), the SOS test, TABLE 8.1

the test for unscheduled DNA synthesis, and the formation of adducts on DNA (see Section 4.4.4), also referred to as “adductomics” [198]. These tests can be applied to a wide variety of experimental systems. Another group of genopathic assays depend on germline mutations and damage to embryos. Almost all of these tests are more expensive than those described above.

8.6.5 Multiplicity of tests and methods for their use None of the laboratory organisms are biologically the same as humans, and so the test systems are only surrogates for tumor formation in humans. As such, no single test has been established as a perfect method for indicating carcinogenic potency in humans. The tendency has been to compare the performances of the various tests and try to establish the best ways of using them. Because of the large number of possible tests, in the 1970s, government agencies suggested specific algorithms for testing (see Ref. [179]).

Suitability of organisms for tests of genetic toxicity and carcinogenesis. Suitability of organism to test of effect

Effect measured

Whole animal

Cells cultured in vitro

Bacteria

Tumor formation

Yes (see Fig. 3.10)

Yes: malignant transformation in vitro

No

Nuclear structural lesions (especially micronuclei)

Yes

Yes

No

Chromosomal aberrations

Yes

Yes

No

Somatic mutations (subcytogenetic damage with phenotypic effect)

Yes, e.g., Big Blue Mutamouse

Yes, e.g., mouse lymphoma test

Yes, e.g., Ames test

DNA damage in extracts of living cells (no phenotypic effect)

Yes, comet assay, SOS test, unscheduled DNA synthesis, adducts on DNA

Yes, various tests

Yes, various tests

Germline mutations

Yes*

No

No

Chromosomal damage to gametes

Yes*

No

No

Lethality to offspring

Yes*

No

No

*In various species including in Drosophila and zebra fish.

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8. Prevention of tumors

An algorithm procedure normally begins with a high-sensitivity, low-specificity test. After that, there are successive tests which have progressively higher specificity. For example, in an algorithm procedure for carcinogenesis, the primary screening tests might be (i) A bacterial mutagenesis test (e.g., Ames), (ii) A mammalian cell culture mutagenesis test, (iii) An in vivo chromosomal test (see in Table II, Ref [179]). If the substance produced a positive result in (i) or (ii), it would be tested secondarily by a Drosophila embryo lethality assay. If a positive result was found in that test, the substance would be subjected to a tertiary test of cancer bioassay in animals. If the substance produced a positive result in (iii), it would be tested with cancer bioassays and rodent embryo lethality assays. The general outcome of the research is that many tests have various degrees of sensitivity and specificity for carcinogenic effects in humans, and no single test is fully satisfactory in either 100% sensitivity or 100% specificity. Because of this, these algorithms were found to be of restricted value in practice. As a result, many agencies require only that examples from a list of kinds of test (i.e., a battery) be performed, without rigid ranking as to precedence. The results of laboratory tests are also often used in conjunction with epidemiological data for assessments of possible carcinogenicity for humans. The IARC publishes monographs on individual substances or groups of substances [199]. Their method for evaluating carcinogenic risks integrates evidence of all relevant kinds: An interdisciplinary Working Group of expert scientists meets at IARC in Lyon, France, for eight days. The Working Group reviews the published studies and evaluates the weight of the evidence that an environmental factor can increase the risk of cancer. After performing and discussing a critical review of the

published scientific evidence, the Working Group formulates the evaluations. As a result, each agent is classified into one of five categories. [200].

The process does not involve a prescribed set of tests. The US Environmental Protection Authority has published (2005) its guidelines [201] which are similar to the IARC methods.

8.6.6 Co-carcinogens and other multifactorial circumstances A difficult aspect of experimental systems for testing individuals is the issue of cocarcinogenesis and multifactorial etiologies [202,203] (see also Chapter 4). In a test system, this may mean the necessary sequential or concurrent application of many different substances. To test for these possibilities, large numbers of experiments would be necessary. If whole animal models are used, the cost would probably be substantial.

8.6.7 Noncorrelation of relative potencies for carcinogenesis in relation to other effects The fact that different species have different susceptibilities to carcinogens is described in Section 4.2.3. Here, it is noted that there are species differences in the susceptibilities to cellular abnormalities which are taken as surrogates for carcinogenesis. The phenomenon of noncorrelating cell biological tests has been extensively studied in relation to alkylating agents. Different species have been used for each test: for example, cells in culture for chromosomal aberrations, bacteria (as in the Ames test described above) for mutagenicity, and a mammalian species (such as the mouse) for carcinogenicity. The results were overall, that no constant association between carcinogenic and other potencies could be established for these agents [204].

8.7 Human lesion and genetic screening programs and their efficacies in preventing deaths from tumors

This apparent noncorrelation of relative genopathic potencies has been found with many other chemicals. For example, ethylbenzene, which is carcinogenic in rats, has been found to be nonmutagenic in bacteria and yeast and nonclastogenic (i.e., does not cause chromosomal aberrations, see Section 4.1.1) in Chinese hamster ovary cells [205]. Phenolphthalein induces tumors in rodents and is clastogenic in some experimental test systems but does not to form adducts on DNA and is not mutagenic in bacterial and mammalian cell models [206]. Acrylonitrile is mutagenic in bacterial assays, but not clastogenic in cultured mammalian cells [207]. Aniline compounds which are carcinogenic in Fischer 344 rats have been found not to be mutagenic in most test systems, and only clastogenic in some systems in the highest doses [208]. These findings suggest strongly that all mutagens may not be carcinogens [209].

8.6.8 Possible future experimental methods The previous sections show that perfect methods for predicting carcinogenic potencies of chemicals for humans are still lacking. This may be because, if any agent is found to have an effect in a nonhuman experimental system, the effect may not be valid for human beings because of toxicokinetic differences between species (Appendix A3.5.1). For human in vitro cellular systems, positive results may not be valid for the whole human because the cells in culture are deprived of defensive barriers (Appendix A3.5.1). It is possible that a series of cell-free assay systems might be optimal. These might involve the effects of test substances in cell-free assays of human genome processes for fidelity of replication of DNA, chromosomal aberrations, and cytoskeletal-membrane cohesion among possibly other biochemical phenomena known to occur early in malignant change of cells.

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8.7 Human lesion and genetic screening programs and their efficacies in preventing deaths from tumors 8.7.1 Overview Some aspects of screening programs are outlined in Section 7.2.3. The screening methods may consist of physical examination and imaging of organs, measurement of a relevant “biomarker” (see Appendix A6) in a tissue, or body fluid, or genetic testing (see below). For efficiency, screening is usually only applied to subgroups of the whole population. The subgroups may be based on age or, to lesser degrees, other risk factors such as relevant family history [210]. The process of developing a screening program involves (i) Developing the technology for the test. (ii) Validating the test in terms of sensitivity (i.e., to avoid false negative results) and specificity for a particular type of tumor (i.e., to avoid false positive results). (iii) Evidence that a positive result will change the circumstances of the individual. This may mean the availability of a suitable treatment or indication for the adoption of some lifestyle change. (iv) Assessment of the proportion of the screened population found to be positive. (v) Related to (iv) are costebenefit estimations. “Costs” include financial costs of implementing the population testing and psychological costs for individuals, in particular those provided with inconclusive test results.

8.7.2 For carcinoma of the bronchi Screening either by chest X-rays or sputum cytology has resulted in little improvement in mortality from these diseases [211]. Currently, only low-dose CT is used for screening, with strict qualifications: history of 30 þ pack years,

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8. Prevention of tumors

smoking at time of screening or have quit within the previous 15 years, and age 55e80. A pack year is smoking an average of one packet per day for 1 year [212]. In one study, approximately 60% of the participants had nodules which required “tracking” (repeat CTs for growth). 2% of the participants required biopsy, of which three-quarters (1.5% of the whole group) had cancer [213]. The burden of this screening indicated in this study is that approximately 55% of the enrollees in the study had value-less follow-up studies (the precise number is not clear) with associated medical and other expenses (see in Chapter 20). Attempts have been made to improve distinction between malignant and nonmalignant nodule images, but with little success [214]. To cast further doubt on the value of screening by imaging, the CDC criteria (above) for screening have been suggested to be too strict because they exclude 50% of early lung cancer cases in the population [215]. A study from Germany showed that the screening costs “five years of annual screening resulted in a 9.7%e12.8% lung cancer mortality reduction,” and “16,754e23,847 euro per life year gained and 155,287e285,630 euro per averted lung cancer death” [216].

8.7.3 For colorectal carcinoma Since the 1970s, screening of individuals older than 60 years has been undertaken based on tests for occult blood in the feces. The sensitivity of the test has been improved by technological improvements [217,218]. The test is said to reduce mortality of colorectal carcinoma by approximately 18% [219]. The other test is by colonoscopy or flexible sigmoidoscopy. This has been used for the detection of carcinomas in patients with polyposis syndromes (see Sections 5.3.2 and 5.5.2). As a test in unpredisposed, asymptomatic individuals over 60 years of age, “once-only” flexible

sigmoidoscopy is used as a screening method. This technique is much more expensive than fecal occult blood testing but has the advantage that it detects small lesions including polys as well as large lesions. The method is said to reduce mortality of colorectal carcinoma by approximately 28%, although operative complications such as perforation of the bowel can occur [220].

8.7.4 For carcinoma of the breast Screening for early tumors of the breast began in the 1950s. At first, detection of suspicious masses was by physical examination by a physician or by the woman herself. However, as imaging technology improved, radiology and ultrasound techniques have become the main method of detecting abnormal masses [221]. Improvements of 30%e50% in mortality from the disease have been widely reported. However, the precise degrees of the contribution of screening to these improvements are controversial. The difficulties in conducting clinical trials have included (i) The long course of the disease (the disease may be latent for decades before reappearing in aggressive formdsee Section 8.4), (ii) The changing imaging criteria for lesions to be further assessed, (iii) The changes in histopathological criteria of malignancy, and (iv) The rapid developments in new therapies for the disease [221,222]. For example, in screening for breast cancer, mammography usually will detect more lesions than physical examination (see Ref. [222]) (Table 8.2).

8.7.5 For carcinoma of the prostate Screening by digital rectal examination was carried out for several decades, but had poor sensitivity [223].

8.7 Human lesion and genetic screening programs and their efficacies in preventing deaths from tumors

TABLE 8.2

245

Sensitivities and specificities of screening methods based on detection of early pathological lesions.

Tumor

Screening procedure

Sensitivity/specificity

Carcinoma of lung

CXR  sputum cytology

Poor/poor

a

Low-dose spiral CT

High/moderate

Carcinoma of cervix

Cells from the cervix examined by microscopy

High/high

Carcinoma of breast

Physical examination

Low-moderate/low a

Moderate/moderate

Radiological appearances Carcinoma of colorectum

Carcinoma of prostate

b

Fiber optic visualization of organ

Very high/very high

Fecal occult blood

Moderate/moderate

Specific antigens in serum

Sensitive for metastatic tumor only Low levels in serum have low specificity

Digital palpation of prostate

Sensitive for large local tumors only Moderate-high specificity

a b

Costly. Very costly.

Currently, serum prostate-specific antigen (PSA) as a screening test is controversial, as described in Sections 7.2.3 and 7.4.1 (see also Ref. [224]). The test has two limitations: (i) Nontumorous diseases of the prostate can raise the serum PSA, (ii) The range of levels of PSA in men with carcinoma of the prostate overlaps the PSA levels in healthy men and in men with nontumor prostate disease, (iii) High levels of PSA in the serum indicate disease which has already spread in the body, and hence is not “early” as required by the objectives of a screening program. Improved methods are needed [225].

8.7.6 For carcinoma of the cervix Since its introduction in the 1950s, screening for abnormal cells in this organ has been associated with approximately 70%e80% falls in deaths from carcinoma of the cervix in Western countries [226,227]. This has occurred despite

an apparent marked rise in the incidence of infection of the cervix with human papilloma virus. The virally infected cells are histologically abnormal and are destroyed by the treatments. The costs of the screening programs, however, are too great for poorer countries, so that in those regions, no such fall in mortality from cervical cancer has occurred [228].

8.7.7 Other biomarker or lesional screening Serum CA125 levels and transvaginal ultrasound studies have been proposed for screening for ovarian carcinoma but lacks sensitivity and specificity [229]. Regular skin examination has been recommended for early detection of malignant melanomas in susceptible people [230]. However, a review in 2016 by the US Preventive Services Task Force suggested that this screening did not improve mortality, and the benefits did not outweigh the harms [231].

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Regular relevant imaging for individuals with hereditary predispositions to particular tumors, e.g., renal cell carcinoma, is generally accepted are part of proper management.

8.7.8 Screening for germline genetic predispositions/personalized disease prevention through genomic studies (a) Selective gene sequencing Low-penetrance germline predispositions to tumors and the possibility of identifying combinations of germline lesions are discussed in Section 5.9. Such data could be useful in many settings. For example, if there were to be found a “diagnostic combination of genomic lesions” for carcinoma of the colon and rectum, the individual would be able to go onto a colonoscopic surveillance program, similar to that for known hereditary predispositions to the tumor (see Section 7.2.3). To date, single gene studies have not provided specific or sensitive data. Studies using new generations of sequencing of mutations in panels of genes have been undertaken [232]. Interpretation of the results remains difficult due to the difficulties in assessing pathogenetic versus nonpathogenetic genomic events (see Appendix A3.5.6) in one gene, let alone multiple genes. At the present time, germline mutations in panels of genes have been reported for many cancer types, including of the lung [233], colorectum [234,235], breast [236], and prostate [237]. At present, no methods or interpretation are available which are sufficiently reliable for decision-making [238,239].

8.7.9 Assessing benefits of screening There are many issues in assessing benefits of screening. Most attention has been given to survival. As is described in the National Cancer Institute document “Crunching Numbers: What Cancer Screening Statistics Really Tell Us” [240], the usual

cited benefits of screening may be due to “leadtime bias” and “length (rate of growth) bias.” In the above publication, Dr Donald Berry, Professor of biostatistics at the University of Texas, is quoted as saying: “With any screening test you’re going to pick up the slowergrowing cancers disproportionately, because the preclinical period when they can be detected by screening but before they cause symptomsd the so-called sojourn timedis longer.” Dr Lisa Schwartz from the Center for Medicine and Media at the Dartmouth Institute explained that if the length time bias is longer than the expected life, of the person, overdiagnosis is achieved. “If the chance of dying from a cancer is small to begin with, there isn’t that much risk to reduce. So the effect of even a good screening test has to be small in absolute terms.” (Quoted in Ref. [240]) (Fig. 8.20). Many of the problems are the same as those for clinical trials (see in Appendix A9.3). First, the participation rate is important. This is the proportion of individuals invited to enter the program who participate. Typically, participation rates vary with the age of the invited person, as well as other factors, such as inconvenience of the test and the expected positive rate (less participation for rarer studies). Because participants sometimes delay entry into the program, or “drop out” from the program, it is optimal to have data on “participant years.” Declines in mortality ratesdthe essential aim of a screening programdare difficult to measure for all the reasons mentioned in Section 7.2. Generally, however, the following might be expected: (i) For tumor types for which no effective treatment is available regardless of stage of disease (see Section 1.3.2), screening should have no effect on mortality of the tumor type if incidence rates also remain unchanged. (ii) For tumor types for which effective treatment is available, screening leading to earlier treatment should cause a decline in mortality.

8.8 Cancer-preventative drugs: benefits and potential dangers

247

Lead-me bias Without screening Cancer diagnosed because of symptoms at age 67 y Dead at age 70 y Cancer starts

5-year survival = 0%

With screening Cancer diagnosed because of screening at age 60 y Dead at age 70 y Cancer starts

5-year survival = 100%

Overdiagnosis bias Without screening 5 years later 1000 people with progressive cancer

400 alive

5-year survival = 400 = 40% 1000

600 dead

With screening

2000 people with nonprogressive cancer

2000 alive

5 years later 5-year survival = 2400 = 80% 3000

1000 people with progressive cancer

400 alive 600 dead

In lead-me bias, survival rates are inflated by earlier diagnosis even if mortality remains; in overdiagnosis bias, survival rates are inflated by the detecon of nonprogressive cancer even if mortality remains unaltered. Figure reproduced from reference 2 with premission of the American Medical Associaon.

FIGURE 8.20 Screening statistics. Source: Wegwarth O, Schwartz LM, Woloshin S et al. Do physicians understand cancer screening statistics? A national survey of primary care physicians in the United States. Ann Intern Med 2012 Mar 6;156(5):340e9.

(iii) Delays in the reduced mortality becoming evident may vary according to the underlying aggressiveness of the type of tumor. Thus, if untreated cases of a tumor type are liable to die within months, a curative therapy will cause a fall in mortality within months. However, if untreated cases of a tumor type usually survive many years, then the fall in mortality will only be detected after a corresponding period of time.

8.7.10 Harms of screening These depend on the particular method of screening and the particular type of tumor involved. Most data have concerned screening for breast cancer [241e243]. Harms can be classified as resulting from (i) False positive results leading to unnecessary treatment,

(ii) Indecisive test results (i.e., as expressed in “maybe”/“suspicious of . ”) leading to unnecessary further investigations, (iii) Anxiety, reduced quality of life, and economic losses which may be associated with (i) and (ii). (iv) Unreimbursed medical costs of screening tests, as well as other “out-of-pocket” expenses (see in Chapter 20).

8.8 Cancer-preventative drugs: benefits and potential dangers 8.8.1 General The objectives of this prophylaxis is the prevention of carcinogenesis, or prolongation of phase of conversion of benign tumors to the malignant (i.e., invasive) stage by prior by intervention with drugs [244].

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This is an important topic because of the large number of individuals who are known to have a greater-than-normal likelihood of developing tumors. These individuals may have either (i) Prior exposure to a known carcinogen, e.g., tobacco smoker who has not developed tumor, (ii) An unresectable “premalignant” disease or histological change in an organ, e.g., idiopathic ulcerative colitis, which predisposes to carcinoma of the colon and rectum. (iii) A known hereditary predisposition, There has been considerable study of potential cancer-preventative drugs, but at the time of writing, fewer than 20 drugs have been approved by the FDA [245].

8.8.2 Difficulties in assessing complex mixtures At the outset, it should be noted that there are great difficulties in assessing the cancerpreventative value of complex mixtures, especially if they are nonprescription substances and widely available in the community. This particularly applies to the substantial literature concerning the possible cancer-preventive potencies of dietary factors, e.g., Refs. [139,246,247]. They are difficult to assess because of the lack of chemical specificity. It is particularly difficult with the lifestyle factors. As an example, suggestions of the benefits of drinking tea can be considered. Among many potential sources of error, it is difficult to determine whether drinking this tea actually does protect against tumors or is merelydin the particular trial, but not necessarily invariablyd associated with some carcinogenic factor which tea drinkers might habitually avoid. Another possibility is that certain kinds of tea might contain both carcinogens and anticarcinogens.

This remainder of this section deals only with specific chemicals [248,249].

8.8.3 Classification of cancerpreventative drugs Cancer-preventative drugs have been considered for many years, and many potential modes of action have been identified. Their mechanisms of action have been divided into “blocking,” “maturing,” “suppressive,” and “miscellaneous” kinds [250,251]. (a) Preventing carcinogens reaching susceptible cells These have been called “blocking” agents (see Ref. [250]). They may act on any of the “toxicokinetic/-dynamic factors” (see Appendix A3.1). Sunscreen products for the prevention of skin cancers are a major example. A less established example is vegetable fiber in the prevention of colorectal carcinoma. Dietary fiber is said to “trap” carcinogens in the lumen of the colon. Within the cells, some blocking agents may prevent activation of precarcinogens, and others may enhance detoxification systems of the target cell. (b) Preventing “maturation” of susceptible cells These “maturation” agents are controversial (see Ref. [250]). It has been suggested, for example, that the terminal ducts of the breast in nulliparous women are “less mature” and hence more liable to carcinogens than terminal ducts which have been “matured” through pregnancy. (This is to account for the higher incidence of breast carcinoma in nulliparous vs. child-bearing women.) None of these concepts have been proven in a biochemical sense, because the nature of the supposed carcinogens is unknown, and the toxicokinetic or -dynamic aspects of the supposed “immaturity” of the ducts are not established (Fig. 8.21).

8.8 Cancer-preventative drugs: benefits and potential dangers

249

A. Agents which prevent acvated carcinogens reaching normal cells in the body (a) (a) Through skin (b) Through the lungs (c) Through the stomach (b)

(b)

(d) By the liver (e) By the kidneys

(f) By the liver (g) By the kidneys

(d, f)

(e, g)

(c)

(e, g)

B. Agents which act on tumorous or pre-tumorous lesions. They either prevent benign tumors progressing to malignant ones, or malignant tumors becoming more malignant. They may have the either maturaonal or suppressive mechanisms: (untreated)

“Progression”: cells worsen in their morphological and behavioral features

Maturaonal “Maturaon”: cells revert to the morphological and behavioral features of the parent cells Suppressive The changes of progression are suppressed

FIGURE 8.21

Potential mechanisms of cancer-preventative drugs.

(c) “Suppressive agents” “Suppressing” agents (see Ref. [250]) are aimed at preventing benign tumors progressing to malignant ones or malignant tumors becoming more malignant. Proposed mechanisms include the following:

(i) Induction of “differentiation,” (ii) Preventing further genopathic events, (iii) Selectively inhibit proliferation of malignant cells, (iv) Inhibition of possible cancer-associated inflammatory mechanisms, such as the arachidonic acid cascade.

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The “miscellaneous” group includes various dietary agents which have known biochemical activities, such as inhibition of proteases, but whose pharmacology seems not to be the same as the other groups. Another classification has a biochemical approach [252]. Drugs are classified into those which cause (i) Reduction of endogenous production of carcinogens (ii) Reduction in amounts and absorption of exogenous carcinogens (iii) Prevention of activation of precarcinogens (iv) Inhibition of binding of carcinogens to DNA (v) Inhibition of tumor promoters and cell proliferation generally (vi) Agents said to have antitumor effects, but by unknown mechanisms (e.g., protease inhibitors, organosulfur compounds, polyphenols, etc.)

8.8.4 Laboratory assessments of these agents As with drugs for treating cancers, drugs for prevention of cancer must first be studied with laboratory tests for efficacy, toxicokinetics, and side effects [253]. Many studies examine reductions in the rates of tumors caused by specific carcinogens or the inhibition of “genopathic effects” induced by known carcinogens in animal, mammalian cell culture, and bacterial test systems [254,255] (see also Section 7.1.2). However, these types of study introduce two sets of toxicokinetic and -dynamic variables (see Section 7.2). Hence, the validity of the genopathic model for human carcinogenesis must be established, and similarly, the validity of the action of the putative cancer-preventative drug must be confirmed.

8.8.5 Difficulties of clinical trials of these agents Chemo-preventative drugs are used as diseasemodifying substances, and after laboratory testing

(previous subsection), they must be subject to the same stringent clinical trials as are drugs against tumor cells in the body. Clinical trials of chemo-preventive drugs, however, are particularly difficult owing to the long observation periods and large study populations required to measure cancer incidence reduction. Some trials have concentrated on using reversions of “biomarkers” (defined as morphologic and/or molecular alterations in tissue between initiation and tumor invasion) (Ref. [248]). Nevertheless, valid chemical targetsdin respect of the supposed events of this transition from a noninvasive to an invasive state of individual lesionsdfor the chemo-preventative agents have not been clearly identified.

8.8.6 Currently recommended cancerpreventative drugs for particular tumor types In general, the focus of these studies has been on antihormonal or antiinflammatory drugs [256]. However, because each tumor type is a separate disease, and the cells involved have different toxicokinetic properties, different drugs are probably required for each type. At the time of writing, cancer-preventative agents have been investigated in relation to the common malignancies as follows. (a) Lung carcinoma In the 1990s, beta-carotene, retinoic acid, vitamin E, and N-acetylcysteine were tested in clinical trials. Beta-carotene was found to increase the incidence of cancers in tobacco smokers, while the other agents had no effect. Still other agents have been subject to trials, but without definite benefits being observed [257]. (b) Breast carcinoma Estrogen-receptor inhibitors, especially tamoxifen, have been shown to be effective in

8.9 Barriers to prevention

251

inhibiting the development of carcinoma of the breast, especially in women with positive family histories [258].

without access to the Internet can be deprived of this information should they wish to obtain it.

(c) Colorectal carcinoma

8.9.2 Failure to access or act on information

Various antiinflammatory drugs are presently being tested for preventative effects on this disease. The rationale appears to be related to the fact that carcinoma of the colon is a relatively common complication of idiopathic ulcerative colitis. No convincing evidence of the value of antiinflammatory drugs has been reported [259]. (d) Prostatic carcinoma Most studies have focused on possible preventive effects of vitamin E, selenium, and the antiandrogenic drugs 5-alpha-reductase inhibitors. None have been shown to be beneficial in clinical trials [260].

8.9 Barriers to prevention Despite decades of public health attempts to prevent cancers by lifestyle changes in the population, success has been only limited. The literature on barriers to actualizing behavioral change in relation to specific preventative measures, especially in specific ethnic or socioeconomic groups is noteworthy. Additional issues are low participation rates in prevention trials and low long-term adherence to behavioral change [1, 261]. The following sections provide the classification of general barriers.

8.9.1 Lack of information Many government and nongovernment health agencies and organizations publish material on cancer prevention, free online for the general public, as well as for health professionals. The quantity and quality of the information is probably often better than teaching in many medical schools worldwide. Only persons

Thun et al. [262] list the following psychological barriers to preventative action by informed individuals: a. Success is invisible b. Lack of drama makes prevention less interesting c. Statistical lives have little emotional effect d. Long delay before rewards appear e. Benefits do not (often) accrue to the payer f. Advice is inconsistent or changes g. Persistent behavior change may be required h. Bias against errors of commission i. Avoidable harm is accepted as normal (and thus not remediated) j. Expected to produce a net financial return, unlike treatment and its associated costs k. Commercial interests may conflict with disease prevention l. Advice may conflict with personal religious beliefs or cultural practices. To these may be added: (i) Reluctance to consider an unpleasant topic. (ii) Faith in personal invulnerability: “my father smoked and didn’t die of lung cancer, so why should I stop smoking?” (iii) Confusing information/doubtful benefit. Certain forms of prevention, such as cessation of tobacco smoking, are clear cut. However, matters such as “healthy diet” are less clearly translated into behavioral change. For example, advice “Eat more a, b, c, etc., foods” is vague. (iv) Alarm fatigue: too much “crying wolf.” The public media report latest literature almost on a weekly basis. Cumulatively, many aspects of human life are portrayed as cancer “risks.”

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(v) Peer pressure. Cessation of smoking or alcohol use may be unacceptable to the social life of many people. (vi) Unattractive aspects of the screening procedure. This applies especially to cervical and breast studies, as well as fecal specimen collections for colorectal cancer. (vii) Pleasures foregone in observing preventative measures. Many people enjoy tobacco smoking, alcohol use, sugary drinks, red meat, etc. (viii) Cost of following advice: Actioning some preventative measures, for example, ceasing tobacco smoking, is clearly financially beneficial to the individual. For dietary changes, it is relevant that fresh food is more expensive than tinned or otherwise preserved food. The World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR, see above) current dietary recommendation of “eating at least five portions/servings of a variety of nonstarchy vegetables and or fruits every day” might be too expensive for much of the population, even in highly developed countries, to contemplate. Participation in screening trials may incur travel and other unreimbursed costs to the individual.

8.10 Summary of translational issues in cancer prevention 8.10.1 Lack of data on mutation accumulation over lifetimes of individuals This issue requires repeated samples of tissues from individuals over time. For example, it would be interesting to compare the genomes of nonlymphoid leukocytes (DNA stored) from cord blood of neonates, with the genomes of nonlymphoid leukocytes of the same individual at intervals, for example, every decade. This would be a long-term prospective study.

8.10.2 Lack of data on bioaccumulations (a) Maximum permissible exposures/ “levels” As noted in Section 4.1.3, in humans, very few carcinogens are known which can cause tumors in a single dose of exposure. Once a “biological gradient relationship” of exposure to putative carcinogen and incidence of tumor type has been established (see Section 8.1.4), the question in prevention is “what is an acceptable dose and/or exposure rate.” For many known chemical carcinogens, low doses with infrequent episodes of exposure may have no effect. As a result, while identifying relationships between dose ratedtumor formation, there may be difficulty nevertheless in establishing how much carcinogenic exposure is “harmless,” “acceptable,” or “unacceptable” [263e266,267]. Examples are in workers with radio-active substances. This is because human populations are exposed to “background” ionizing radiations, comprising cosmic rays and naturally occurring radioactive elements in minerals, such as thorium in granite [173]. All of the points in the previous section have enormous influence on regulatory bodies dealing with occupational health. The application of this is in establishing “maximum acceptable levels” of exposures. At the time of writing, the National Institute for Occupational Safety and Health is reviewing its methodology and recommendations concerning human carcinogens [268].

8.10.3 Vagueness in the biology and mutagenic implications of “lifestyle” factors

8.10.4 Data currently unavailable (a) With age by comparison of early life and latelife sample sequencing

References

(b) As in (a) but comparing also smokers versus nonsmokers (c) As in (b) but also comparing different kinds of cells in the body (d) Comparative sequencing of identical twins, if they have different habits, e.g., smoker versus nonsmoker

[12]

This is not possible at the present time, because sequencing techniques are not yet sufficiently reliable. Effects of biobanking techniques on DNA sequencing is also uncertain [269].

[14]

[13]

[15]

[16]

References [1] Meyskens FL, Mukhtar H, Rock CL, et al. Cancer prevention: obstacles, challenges, and the road ahead. JNCI 2016;108:djv309. https://doi.org/10.1093/jnci/ djv309. [2] Thomas F, Roche B, Beata U. Intrinsic versus extrinsic cancer risks: the debate continues. Trends in Cancer 2016;2:68e9. [3] https://www.dartmouth.edu/wtoxmetal/arsenic/ history.html. [4] Hughes MF, Beck BD, Chen Y. Arsenic exposure and toxicology: a historical perspective. Toxicol Sci 2011; 123(2):305e32. [5] Shimkin MB. U.S. Department of Health, Education and Welfare, public health service. National Institutes of Health; 1977. p. 179. [6] Hutchinson J. Arsenic-keratosis and arsenic-cancer. Trans. Path. Soc. (London) 1888;39:352. [7] Huff J, Chan P, Nyska A. Is the human carcinogen arsenic carcinogenic to laboratory animals? Toxicol Sci 2000;55(1):17e23. [8] Brown JR, Thornton JL. Percivall Pott (1714-1788) and chimney sweeps’ cancer of the scrotum. Br J Industrial Med 1957;14(1):68e70. [9] Miller BG, Cowie H, Middleton WG, et al. Epidemiologic studies of Scottish oil shale workers: III. Causes of death. Am J Ind Med 1986;9(5):433e46. [10] Yamagiwa K, Ichikawa K. Experimental study of the pathogenesis of carcinoma. The J Cancer Research 1918;3(1):1e29. [11] Finlayson-Pitts BJ, Pitts JN. Airborne polycyclic aromatic hydrocarbons and their derivatives: Atmospheric chemistry and toxicological implications. In: Finlayson-Pitts BJ, Pitts JN, editors. Chemistry of the upper and lower atmosphere. Academic Press; 2000. p. 436e546.

[17] [18] [19]

[20]

[21]

[22] [23]

[24]

[25] [26] [27]

[28]

253 McMahon B. Accomplishments in cancer epidemiology. In: Adami H-O, Hunter D, Trichopoulos D. (eds) “Textbook of cancer epidemiology”, Oxford University Press Online. DOI:10.1093/acprof:oso/ 9780195311174.003.0001. US Department of Health and Human Services. National Toxicology program. Report on carcinogens. 14th ed. 2016. https://ntp.niehs.nih.gov/ntp/roc/ content/profiles/dimethylaminoazobenzene.pdf. Shimkin MB. Contrary to nature. DHEW publication No. (NIH) 76-720. 1977. p. 247e8. Lorenz E. Radioactivity and lung cancer; a critical review of lung cancer in the miners of Schneeberg and Joachimsthal. J Natl Cancer Inst 1944;5:1e15. “Health risks of radon and other internally deposited alpha-Emitters: Beir IV.” national research council (US) committee on the biological effects of ionizing radiations. Washington (DC): National Academies Press (US); 1988. https://www.ncbi.nlm.nih.gov/ books/NBK218126/. Thorotrast: Wikipedia https://en.wikipedia.org/ wiki/Thorotrast (Accessed Oct 2018). Hueper WC. Occupational tumors and allied diseases. Springfield IL: Charles C. Thomas; 1942. p. 644. Macmahon HE, Murphy AS, Bates MI. Endothelialcell sarcoma of liver following thorotrast injections. Am J Pathol 1947;23(4):585e611. Agency for toxic substances and disease registry, Division of Toxicology and Human Health Sciences, USA. https://www.atsdr.cdc.gov/toxfaqs/tfacts147. pdf. Science Museum Group. William R Warner Company Limited. http://collection.sciencemuseum.org.uk/ people/cp111178/william-r-warner-and-companylimited [accessed Mar 2019]. Hueper WC. Occupational tumors and allied diseases. Springfield IL: Charles C. Thomas; 1942. Hueper WC. Environmental and occupational cancer. Public Health Reports, Federal Security Agency, Public Health Service; 1948. Supplement 209. Hueper WC. A quest into the environmental causes of cancer of the lung. Washington DC: US Government Printing Office; 1956. p. 9e10. Public Health Service Publication No. 452. Hueper WC, Conway WD. Chemical carcinogenesis and cancer. Springfield IL: C. C. Thomas; 1964. Carson R. Silent spring. Houghton Mifflin; 1962. Bonser GM, Faulds JS, Stewart MJ. Occupational cancer of the urinary bladder in dyestuffs operatives and of the lung in asbestos textile workers and iron-ore miners. Am J Clin Pathol 1955;25(2):126e34. Schottenfeld D, Fraumeni Jr JF, editors. Cancer epidemiology and prevention. 3rd ed.. Oxford: Oxford University Press; 2006. p. 185.

254

8. Prevention of tumors

[29] Proctor RN. The anti-tobacco campaign of the Nazis: a little-known aspect of public health in Germany, 1933e45. BMJ 1996;313:1450. [30] Doll R, Hill AB. The mortality of doctors in relation to their smoking habits. Br Med J 1954;328(7455): 1529e33. [31] Doll R, Hill AB. Lung cancer and other causes of death in relation to smoking; a second report on the mortality of British doctors. Br Med J 1956;2(5001):1071e81. [32] United States. Surgeon General’s Advisory Committee on smoking and health, and United States. Public health Service. Office of the Surgeon general. Smoking and Health. United States. Public Health Service Publication No. 1103. Office of the Surgeon General; Report of the Advisory Committee to the Surgeon General of the Public Health Service, 1964. [33] Craddock PT. Mining and metallurgy, chapter 4. In: Oleson JP, editor. The oxford handbook of engineering and technology in the classical world. Oxford University Press; 2008. p. 111e2. [34] Kanavy HE, Gerstenblith MR. Ultraviolet radiation and melanoma. Semin Cutan Med Surg 2011;30(4):222e8. [35] World cancer report 2014. World Health Organization; 2014. pp. [Chapter 5].14. [36] Azoury SC, Lange JR. Epidemiology, risk factors, prevention, and early detection of melanoma. Surg Clin 2014;94(5):945e62 [vii]. [37] Burnett ME, Wang SQ. Current sunscreen controversies: a critical review. Photodermatol Photoimmunol Photomed 2011;27(2):58e67. [38] K€ utting B, Drexler H. UV-induced skin cancer at workplace and evidence-based prevention". Int Arch Occup Environ Health 2010;83(8):843e54. [39] American Association of Dermatology. Spot Me. Skin cancer screening. https://www.aad.org/public/ spot-skin-cancer/programs/screenings/30-years-ofskin-cancer-awareness. [40] Viola PL, Bigotti A, Caputo A. Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res 1971;31(5):516e22. [41] Lee FI, Harry DS. Angiosarcoma of the liver in a vinylchloride worker. Lancet 1974;1(7870):1316e8. [42] Jastreboff AM, Cymet T. Role of the human papilloma virus in the development of cervical intraepithelial neoplasia and malignancy. Postgrad Med J 2002;78: 225e8. [43] Frazer IH. Development and implementation of papillomavirus prophylactic vaccines. J Immunol 2014; 192(9):4007e11. [44] Garland SM, Brown DR. Potential of the quadrivalent human papillomavirus vaccine in the prevention and treatment of cervical cancer. Expert Opin Biol Ther 2014;14:527e34. [45] Lees BF, Erickson BK, Huh WK. Cervical cancer screening: evidence behind the guidelines. Am J Obstet Gynecol 2016;214(4):438e43.

[46]

[47]

[48]

[49] [50]

[51]

[52]

[53] [54]

[55]

[56]

[57]

[58] [59]

[60]

[61]

[62]

Hellner K, Dorrell L. Recent advances in understanding and preventing human papillomavirus-related disease. F1000Res 2017:6. pii: F1000 Faculty Rev-269. College of Physicians, Philadelphia; The History of Vaccines. The development of HIV vaccines. https://www.historyofvaccines.org/content/articles/ development–vaccines [accessed Mar 2019]. Kwong PD, Mascola JR. HIV-1 vaccines based on antibody identification, B cell ontogeny, and epitope structure. Immunity 2018;48:855e71. Smith TJ. Exposure assessment for occupational epidemiology. Am J Indust Med 1987;12(3):249e68. Gan LS, Skipper PL, Peng XC, et al. Serum albumin adducts in the molecular epidemiology of aflatoxin carcinogenesis: correlation with aflatoxin B1 intake and urinary excretion of aflatoxin M1. Carcinogenesis 1988;9(7):1223e5. Poirier MC, Santella RM, Weston A. Carcinogen macromolecular adducts and their measurement. Carcinogenesis 2000;21(3):353e9. Phillips DH, Venitt S. DNA and protein adducts in human tissues resulting from exposure to tobacco smoke. Int J Cancer 2012;131(12):2733e53. Garner RC. Assessment of carcinogen exposure in man. Carcinogenesis 1985;6:1071e8. Vineis P, Perera F. Molecular epidemiology and biomarkers in etiologic cancer research: the new in light of the old. Cancer Epidemiol Biomarkers Prev 2007; 16(10). 1954-165. Chen CJ, Hsu LI, Wang CH, et al. Biomarkers of exposure, effect, and susceptibility of arsenic-induced health hazards in Taiwan. Toxicol Appl Pharmacol 2005;206(2):198e206. Maclure M, Katz RB, Bryant MS, et al. Elevated blood levels of carcinogens in passive smokers. Am J Public Health 1989;79(10):1281e4. Bagga D, Anders KH, Wang HJ, et al. Organochlorine pesticide content of breast adipose tissue from women with breast cancer and control subjects. J Natl Cancer Inst 2000;92(9):750e3. Choy WN. Genetic Toxicology and cancer risk assessment. New York, NY: Marcel Dekker; 2001. Wang X, Chorley BN, Pittman GS, et al. Genetic variation and antioxidant response gene expression in the bronchial airway epithelium of smokers at risk for lung cancer. PLoS One 2010;5(8):e11934. Wild CP, Pisani P. Carcinogen-DNA and carcinogenprotein adducts in molecular epidemiology. IARC Sci Publ 1997;142:143e58. Farmer P, Singh R. Use of DNA adducts to identify human health risk from exposure to hazardous environmental pollutants: the increasing role of mass spectrometry in assessing biologically effective doses of genotoxic carcinogens. Mutat Res 2008;659:68e76. Armstrong B, Doll R. Environmental factors and cancer incidence and mortality in different countries,

References

[63]

[64] [65] [66] [67]

[68]

[69] [70]

[71]

[72] [73]

[74] [75] [76] [77] [78]

[79]

[80]

with special reference to dietary practices. Int J Cancer 1975;15:617e31. http://www.cancer.org/acs/groups/content/@epide miologysurveilance/documents/document/acspc028314.pdf. Doll R. Strategy for detection of cancer hazards to man. Nature 1977;265:589e96. Mendelson RW. Betel nut chewer’s cancer. US Armed Forces Med J 1951;2(9):1371e5. Friborg JT, Melbye M. Cancer patterns in Inuit populations. Lancet Oncol 2008;9(9):892e900. Williams H, Powell IJ. Epidemiology, pathology, and genetics of prostate cancer among African Americans compared with other ethnicities. Methods Mol Biol 2009;472:439e53. Bei JX, Jia WH, Zeng YX. Familial and large-scale casecontrol studies identify genes associated with nasopharyngeal carcinoma. Semin Cancer Biol 2012;22(2): 96e106. Wild CP. Environmental exposure measurement in cancer epidemiology. Mutagenesis 2009;24(2):117e25. Kuzniarz M, Mitchell P, Cumming RG, et al. Use of vitamin supplements and cataract: the Blue Mountains Eye study. Am J Ophthalmol 2001;132(1):19e26. Open University UK. Epidemiology: an introduction. http://www.open.edu/openlearn/ocw/mod/oucontent/ view.php?id¼3743&printable¼1 [accessed Mar 2019]. NIH PubMed health website https://www.ncbi.nlm. nih.gov/pubmedhealth/PMHT0025838/. Thun MJ, Jemal A. Cancer epidemiology. In: Hong WK, Bast RC, Hait WN et al. (eds). “Holland-frei cancer medicine”, 8th ed.., People’s Medical Publishing House, Shelton CT, pp 371-385. Sedgewick P. Case-controlled studies: advantages and disadvantages. BMJ 2014;348:f7707. Young KJ, Lee PN. Intervention studies on cancer. Eur J Cancer Prev 1999;8(2):91e103. Kleinsmith LJ. Principles of cancer biology. London: Pearson Higher Education; 2005. p. 63. Hill AB. The environment and disease: association or causation? Proc R Soc Med 1965;58(5):295e300. Goodman SN, Samet JM. Causal inference in cancer epidemiology. In: Thun MJ, Linet MS, Cerhan JR, et al., editors. Shottenfeld and Fraumeni: cancer epidemiology and prevention. 4th ed.. New York: Oxford University Press; 2018. p. 100e3. Berlivet L. Association or causation?" the debate on the scientific status of risk factor epidemiology, 1947-c. 1965. Clio Med 2005;75:39e74.  Giroux E. « Contribution a l’histoire de l’epidemiologie des facteurs de risque ». Rev Hist Sci 2011;64(2):219e24 (English translation at:

[81]

[82]

[83]

[84] [85]

[86]

[87]

[88] [89]

[90]

[91]

[92]

[93]

[94]

255 https://www.cairn-int.info/article-E_RHS_642_0219–acontribution-to-the-history-of-risk.htm. Howick J, Glasziou P, Aronson JK. The evolution of evidence hierarchies: what can Bradford Hill’s ’guidelines for causation’ contribute? J Roy Soc Med 2009; 102(5):186e94. Breslow NE, Day NE. Statistical methods in cancer research, vol. 1, the analysis of case-control studies. IARC scientific publication No. 32. Lyon: International Agency for Research on Cancer; 1980. Breslow NE, Day NE. Statistical methods in cancer research, vol. 2, the Design and analysis of cohort studies. IARC publication No. 82. Lyon: International Agency for Research on Cancer; 1987. US National Cancer Institute www.cancer.gov (Accessed Oct 2018). Cancernet e the website of the American Society of Clinical Oncology (ASCO) https://www.cancer.net/ cancer-type-page-category/risk-factors. Gram IT, Little MA, Lund E, Braaten T. The fraction of breast cancer attributable to smoking: the Norwegian women and cancer study 1991e2012. Br J Cancer 2016;115(5):616e23. American Cancer Society: Known and probably human carcinogens. https://www.cancer.org/cancer/ cancer-causes/general-info/known-and-probablehuman-carcinogens.html. World Health Organisation. Cancer, Key facts. http:// www.who.int/mediacentre/factsheets/fs297/en/. CancerNet: Understanding cancer risk. http://www. cancer.net/navigating-cancer-care/prevention-andhealthy-living/understanding-cancer-risk. Spencer JE. Naturally occurring radioactive materials (NORM) in Arizona. Arizona geological survey openfile report 02-13. Arizona Geological Survey; 2002. https://pdfs.semanticscholar.org/004a/5ef7ee1d381 7c62417e96a60438ab797bca5.pdf. Miles JC, Appleton JD, Rees DM, et al (2011). Indicative atlas of radon in Scotland. Chilton, HPA-CRCE023. Available at: www.hpa.org.uk. Samet JM, Cohen AJ. Air pollution. In: Thun MJ, Linet MS, Cerhan JR, et al., editors. Shottenfeld and Fraumeni: cancer epidemiology and prevention. 4th ed.. New York: Oxford University Press; 2018. p. 291e304. Thun ML, Henley SJ, Travis WD. Lung cancer. In: Thun MJ, Linet MS, Cerhan JR, et al., editors. Shottenfeld and Fraumeni: cancer epidemiology and prevention. 4th ed.. New York: Oxford University Press; 2018. p. 291e304. Rivera GA, Wakelee H. Lung cancer in never smokers. Adv Exp Med Biol 2016;893:43e57.

256

8. Prevention of tumors

[95] Cantor KR, Steinmaus CM, Ward MH, et al. Water contaminants. In: Thun MJ, Linet MS, Cerhan JR, et al., editors. Shottenfeld and Fraumeni: cancer epidemiology and prevention. 4th ed.. New York: Oxford University Press; 2018. p. 305e28. [96] Olsson AC, Vermeulen R, Sch€ uz J, et al. Exposureresponse analyses of asbestos and lung cancer subtypes in a pooled analysis of case-control studies. Epidemiology 2017;28(2):288e99. [97] Marsh GM, Riordan AS, Keeton KA, Benson SM. Non-occupational exposure to asbestos and risk of pleural mesothelioma: review and meta-analysis. Occup Environ Med 2017;74(11):838e46. [98] Bernstein D, Dunnigan J, Hesterberg T, et al. Health risk of chrysotile revisited. Crit Rev Toxicol 2013; 43(2):154e83. [99] Gamble J. Risk of gastrointestinal cancers from inhalation and ingestion of asbestos. Regul Toxicol Pharmacol 2008;52(1 Suppl. l):S124e53. [100] Goodman M, Morgan RW, Ray R, et al. Cancer in asbestos-exposed occupational cohorts: a meta-analysis. Cancer Causes Control 1999;10(5): 453e65. [101] Institute of Medicine (US) Committee on Asbestos: Selected Health Effects. Asbestos: selected cancers. Washington (DC): National Academies Press (US); 2006. https://doi.org/10.17226/11665. Available from: https://www.ncbi.nlm.nih.gov/books/ NBK20332/. [102] Bernstein DM. The health risk of chrysotile asbestos. Curr Opin Pulm Med 2014;20(4):366e70. Erratum in Curr Opin Pulm Med. 2015 Jan;21(1):109. Curr Opin Pulm Med. 2014 Sep;20(5):525. [103] Goodman JE1, Peterson MK2, Bailey LA, Kerper LE, Dodge DG. Electricians’ chrysotile asbestos exposure from electrical products and risks of mesothelioma and lung cancer. Regul Toxicol Pharmacol 2014; 68(1):8e15. [104] Churg A. Asbestos fibers and pleural plaques in a general autopsy population. Am J Pathol 1982; 109(1):88e96. [105] Gualtieri AF, Pollastri S, Bursi Gandolfi N, Gualtieri ML. In vitro acellular dissolution of mineral fibres: a comparative study. Sci Rep 2018;8(1):7071. [106] Feder IS, Tischoff I, Theile A, Schmitz I, Merget R, Tannapfel A. The asbestos fibre burden in human lungs: new insights into the chrysotile debate. Eur Respir J 2017;49(6). pii: 1602534. [107] Freeman MD, Kohles SS. Assessing specific causation of mesothelioma following exposure to chrysotile asbestos-containing brake dust. Int J Occup Environ Health 2012;18(4):329e36.

[108] Woitowitz HJ, Baur X. Misleading “New insights into the chrysotile debate”. Pneumologie 2018;72(7): 507e13. [109] Kawakita D, Matsuo K. Alcohol and head and neck cancer. Cancer Metastasis Rev 2017;36(3):425e34. [110] Gapstur SM, Brooks PJ. Alcohol and cancer risk. In: Thun MJ, Linet MS, Cerhan JR, et al., editors. Shottenfeld and Fraumeni: cancer epidemiology and prevention. 4th ed.. New York: Oxford University Press; 2018. p. 213e26. [111] Steevens J, Schouten LJ, Goldbohm RA, et al. Alcohol consumption, cigarette smoking and risk of subtypes of oesophageal and gastric cancer: a prospective cohort study. Gut 2010;59(1):39e48. [112] Phillips BJ, Jenkinson P. Is ethanol genotoxic? A review of the published data. Mutagenesis 2001;16(2): 91e101. [113] Ratna A, Mandrekar P. Alcohol and cancer: mechanisms and therapies. Biomolecules 2017;7(3). [114] Kuhlmann W, Fromme HG, Heege EM, Ostertag W. The mutagenic action of caffeine in higher organisms. Cancer Res 1968;28(11):2375e89. [115] MacMahon B, Yen S, Trichopoulos D, Warren K, Nardi G. Coffee and cancer of the pancreas. N Engl J Med 1981;304(11):630e3. [116] Anderson LN, Cotterchio M, Gallinger S. Lifestyle, dietary, and medical history factors associated with pancreatic cancer risk in Ontario, Canada. Cancer Causes Control 2009;20(6):825e34. [117] Nkondjock A. Coffee consumption and the risk of cancer: an overview. Cancer Lett 2009;277(2):121e5. [118] Wynder EL, Hall NE, Polansky M. Epidemiology of coffee and pancreatic cancer. Cancer Res 1983;43(8): 3900e6. [119] Guertin KA, Freedman ND, Loftfield E, StolzenbergSolomon RZ, Graubard BI, Sinha R. A prospective study of coffee intake and pancreatic cancer: results from the NIH-AARP Diet and Health Study. Br J Cancer 2015;113(7):1081e5. [120] Bradley MC, O’Rourke MA, Cooper JA, et al. Pharmaceutical drugs other than hormones. In: Thun MJ, Linet MS, Cerhan JR, et al., editors. Shottenfeld and Fraumeni: cancer epidemiology and prevention. 4th ed.. New York: Oxford University Press; 2018. p. 411e31. [121] Dalen JE, Dalton WS. Does lowering cholesterol cause cancer? J Am Med Assoc 1996;275(10):67e9. [122] Hicks BM, Filion KB, Yin H, et al. Angiotensin converting enzyme inhibitors and risk of lung cancer: population-based cohort study. BMJ 2018;363:k4209. [123] Cronin-Fenton D. Angiotensin converting enzyme inhibitors and lung cancer. BMJ 2018;363:k4337.

References

[124] Acquavella J, Farmer D, Cullen MR. A case-control study of non-Hodgkin lymphoma and exposure to pesticides. Cancer 1999;86(4):729e31. [125] Greim H, Saltmiras D, Mostert V, Strupp C. Evaluation of carcinogenic potential of the herbicide glyphosate, drawing on tumor incidence data from fourteen chronic/carcinogenicity rodent studies. Crit Rev Toxicol 2015;45(3):185e208. [126] Tarazona JV, Court-Marques D, Tiramani M, et al. Glyphosate toxicity and carcinogenicity: a review of the scientific basis of the European Union assessment and its differences with IARC. Arch Toxicol 2017; 91(8):2723e43. [127] Andreotti G, Koutros S, Hofmann JN, et al. Glyphosate use and cancer incidence in the agricultural health study. J Natl Cancer Inst 2018;110(5):509e16. [128] Saracci R. The hazards of hazard identification in environmental epidemiology. Environ Health 2017; 16(1):85. [129] Clausing P, Robinson C, Burtscher-Schaden H. Pesticides and public health: an analysis of the regulatory approach to assessing the carcinogenicity of glyphosate in the European Union. J Epidemiol Community Health 2018;72(8):668e72. pii: jech-2017-209776. [130] Sugimura T. Past, present, and future of mutagens in cooked foods. Environ Health Perspect 1986;67:5e10. [131] Willett WC, Stampfer MJ, Colditz GA, et al. Relation of meat, fat, and fiber intake to the risk of colon cancer in a prospective study among women. N Engl J Med 1990;323(24):1664e72. [132] Abid Z, Cross AJ, Sinha R. Meat, dairy, and cancer. Am J Clin Nutr 2014;100(Suppl. 1). 386S-93S. [133] WHO. International Agency for Research on Cancer (IARC). Monographs on the evaluation of carcinogenic risks to humans. Red meat and processed meat, vol. 114; 2018. Available at: https://monographs.iarc.fr/ iarc-monographs-on-the-evaluation-of-carcinogenic-risksto-humans-2/. [134] Turner ND, Lloyd SK. Association between red meat consumption and colon cancer: a systematic review of experimental results. Exp Biol Med 2017;242(8): 813e39. [135] Campbell TC. Nutrition and cancer. Nutr Cancer 2017;69:962e8. [136] Lijinsky W. Significance of in vivo formation of Nnitroso compounds. Oncology 1980;37(4):223e6. [137] Burkitt DP. Epidemiology of cancer of the colon and rectum. Cancer 1971;28:3e14. [138] Aune D, Chan DS, Lau R, et al. Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective studies. BMJ 2011;343:d6617.

257

[139] Asano TK, McLeod RS. Dietary fibre for the prevention of colorectal adenomas and carcinomas. Cochrane Database Syst Rev 2002;(2). Art. No.: CD003430. [140] Glade MJ. Food, nutrition, and the prevention of cancer: a global perspective. American Institute for cancer research/world cancer research Fund, American Institute for cancer research, 1997. Nutrition 1999; 15(6):523e6. [141] World Cancer Research Fund/American Institute for Cancer Research. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington, DC: AICR; 2007. Available at: https:// www.wcrf.org/sites/default/files/english.pdf. [142] Norat T, Aune D, Chan D, Romaguera D. Fruits and vegetables: updating the epidemiologic evidence for the WCRF/AICR lifestyle recommendations for cancer prevention. Cancer Treat Res 2014;159:35e50. [143] World Cancer Research Fund/American Institute for Cancer Research. Diet, nurtition, physical activity and cancer: a global perspective. Continuous Update project report. 2018. Available at: https://www. wcrf.org/sites/default/files/Summary-third-expertreport.pdf. [144] Vergnaud AC, Romaguera D, Peeters PH, et al. Adherence to the world cancer research Fund/American Institute for cancer research guidelines and risk of death in Europe: results from the European prospective investigation into nutrition and cancer cohort study1,4. Am J Clin Nutr 2013;97:1107e20. [145] Jankovic N, Geelen A, Winkels RM, et al. Adherence to the WCRF/AICR dietary recommendations for cancer prevention and risk of cancer in elderly from Europe and the United States: a meta-analysis within the CHANCES project. Cancer Epidemiol Biomarkers Prev 2017;26(1):136e44. [146] Turati F, Bravi F, Di Maso M, et al. Adherence to the world cancer research fund/American Institute for cancer research recommendations and colorectal cancer risk. Eur J Cancer 2017;85:86e94. [147] van Kruijsdijk RC, van der Wall E, Visseren FL. Obesity and cancer: the role of dysfunctional adipose tissue. Cancer Epidemiol Biomarkers Prev 2009; 18(10):2569e78. [148] Irigaray P, Newby JA, Lacomme S, et al. Overweight/ obesity and cancer genesis: more than a biological link. Biomed Pharmacother 2007;61(10):665e78. [149] Reddy BS, Narisawa T, Wright P, et al. Colon carcinogenesis with azoxymethane and dimethylhydrazine in germ-free rats. Cancer Res 1975;35:287e90. [150] Vannucci L, Stepankova R, Kozakova H, et al. Colorectal carcinogenesis in germ-free and conventionally

258

[151]

[152]

[153]

[154]

[155]

[156]

[157]

[158] [159] [160]

[161]

[162]

[163] [164]

[165]

[166]

8. Prevention of tumors

reared rats: different intestinal environments affect the systemic immunity. Int J Oncol 2008;32:609e17. Rakoff-Nahoum S, Medzhitov R. Role of Toll-like receptors in tissue repair and tumorigenesis. Biochemistry (Mosc) 2008;73:555e61. Boleij A, Tjalsma H. Gut bacteria in health and disease: a survey on the interface between intestinal microbiology and colorectal cancer. Biol Rev Camb Philos Soc 2012;87(3):701e30. Hullar MA, Burnett-Hartman AN, Lampe JW. Gut microbes, diet, and cancer. Cancer Treat Res 2014;159: 377e99. Luczynski P, McVey Neufeld KA, et al. Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior. Int J Neuropsychopharmacol 2016;19(8). pii: pyw020. Cole P, Mandel JS, Collins JJ. Acrylonitrile and cancer: a review of the epidemiology. Regul Toxicol Pharmacol 2008;52(3):342e51. Demers PA, Boffetta P, Kogevinas M, et al. Pooled reanalysis of cancer mortality among five cohorts of workers in wood-related industries. Scand J Work Environ Health 1995;21(3):179e90. Vaughan TL, Stewart PA, Teschke K, et al. Occupational exposure to formaldehyde and wood dust and nasopharyngeal carcinoma. Occup Environ Med 2000;57:376e84. Alison MR, editor. The cancer handbook. Chichester, UK: Wiley; 2007. p. 869e1190. Part IV. Teicher BA, editor. Tumor models in cancer research. New York, NY: Humana/Springer; 2011. Abate-Shen C, Politi K, Chodosh LA, et al., editors. Mouse models of cancer: a laboratory manual. NY: CSHL Press, Cold Spring Harbor; 2013. Shimizu Y, Nakatsuru Y, Ichinose M, et al. Benzo[a] pyrene carcinogenicity is lost in mice lacking the aryl hydrocarbon receptor. Proc Natl Acad Sci U S A 2000;97(2):779e82. https://doi.org/10.1073/pnas. 97.2.779. Hardisty JF. Factors influencing laboratory animal spontaneous tumor profiles. Toxicol Pathol 1985; 13(2):95e104. Arcos JC, Argus MF, Wolf G. Chemical induction of cancer. Academic Press; 1968. p. 340e463. Calvisi DF, Thorgeirsson SS. Molecular mechanisms of hepatocarcinogenesis in transgenic mouse models of liver cancer. Toxicol Pathol 2005;33(1):181e4. Kersten K, de Visser KE, van Miltenburg MH, Jonkers J. Genetically engineered mouse models in oncology research and cancer medicine. EMBO Mol Med 2017;9(2):137e53. Khaled WT, Liu P. Cancer mouse models: past, present and future. Semin Cell Dev Biol 2014;27:54e60.

[167] Huijbers IJ, Del Bravo J, Bin Ali R, et al. Using the GEMM-ESC strategy to study gene function in mouse models. Nat Protoc 2015;10(11):1755e85. [168] Morton JJ, Bird G, Refaeli Y, Jimeno A. Humanized mouse xenograft models: narrowing the tumormicroenvironment gap. Cancer Res 2016;76(21): 6153e8. [169] Mishra NK, Di Mayorca G. In vitro malignant transformation of cells by chemical carcinogens. Biochim Biophys Acta 1974;355(3e4):205e19. [170] Combes R, Balls M, Curren R, et al. Cell transformation assays as predictors of human carcinogenicity. The report and recommendations of ECVAM workshop 39. ATLA 1999;27:745e67. http://stagingecvam.jrc.it/publication/WorkshopReport39.pdf. [171] Barile FA. Principles of Toxicology testing. 2nd ed.. Boca Raton, FL: CRC Press; 2013. pp. 142e156; 229255. [172] Hynes RO, editor. Surfaces of normal and malignant cells. Chichester UK: John Wiley & Sons; 1979. [173] Borek C. Malignant transformation in vitro: criteria, biological markers, and application in environmental screening of carcinogens. Radiat Res 1979;79(2): 209e32. [174] Vasseur P, Lasne C. OECD detailed review paper (DRP) number 31 on "cell transformation assays for detection of chemical carcinogens": main results and conclusions. Mutat Res 2012;744(1):8e11. [175] DiPaolo JA, Nelson RL, Casto BC. In vitro neoplastic transformation of Syrian hamster cells by lead acetate and its relevance to environmental carcinogenesis. Br J Cancer 1978;38(3):452e5. [176] DiPaolo JA, Casto BC. In vitro carcinogenesis with cells in early passage. Natl Cancer Inst Monogr 1978;48:245e57. [177] Tennant RW. Relationships between in vitro genetic toxicity and carcinogenicity studies in animals. Ann N Y Acad Sci 1988;534:127e32. [178] Santella RM. In vitro testing for carcinogens and mutagens. Occup Med 1987;2(1):39e46. [179] Zeiger E. Historical perspective on the development of the genetic toxicity test battery in the United States. Environ Mol Mutagen 2010;51(8e9):781e91. [180] US Department of Health and Human Services. Food and drug administration. Guidance for industry e S2(R1) genotoxicity testing and data interpretation of pharmaceuticals intended for human use. 2012. http://www.fda.gov/downloads/Drugs/Guidances/ ucm074931.pdf. [181] OECD Guideline for the testing of chemicals. Mammalian Erythrocyte Micronucleus test. Test No. 474. 1997. http://www.oecd.org/chemicalsafety/ risk-assessment/1948442.pdf.

References

[182] http://www.oecd-ilibrary.org/environment/test-no475-mammalian-bone-marrow-chromosome-aberrationtest_9789264071308-en. [183] Norppa H. Cytogenetic biomarkers and genetic polymorphisms. Toxicol Lett 2004;149(1e3):309e34. [184] Loch-Caruso R, Trosko JE. Inhibited intercellular communication as a mechanistic link between teratogenesis and carcinogenesis. Crit Rev Toxicol 1985; 16(2):157e83. [185] Kari G, Rodeck U, Dicker AP. Zebrafish: an emerging model system for human disease and drug discovery. Clin Pharmacol Ther 2007;82(1):70e80. [186] Vogel EW, Nivard MJ, Ballering LA, et al. DNA damage and repair in mutagenesis and carcinogenesis: implications of structure-activity relationships for cross-species extrapolation. Mutat Res 1996; 353(1e2):177e218. [187] OECD Guideline for the testing of chemicals. Mammalian Erythrocyte Micronucleus test. Test No. 487. 2010. http://www.oecd-ilibrary.org/environment/test-no-487-in-vitro-mammalian-cell-micronucl eus-test_9789264091016-en. [188] OECD guideline for the testing of chemicals. In vitro mammalian chromosomal aberration test. 2014. Test No. 473, http://www.oecd-ilibrary.org/environment/test-no-473-in-vitro-mammalian-chromosomalaberration-test_9789264224223-en. [189] Bonassi S, El-Zein R, Bolognesi C, et al. Micronuclei frequency in peripheral blood lymphocytes and cancer risk: evidence from human studies. Mutagenesis 2011;26(1):93e100. [190] OECD guideline for the testing of chemicals. In vitro mammalian cell gene mutation test. 1997. Test No. 476, http://www.oecd.org/chemicalsafety/riskassessment/1948426.pdf. [191] Lloyd M, Kidd D. The mouse lymphoma assay. Methods Mol Biol 2012;817:35e54. [192] Ames BN, Durston WE, Yamasaki E, et al. Carcinogens are mutagens: a simple test system combining liver homogenates for activation and bacteria for detection. Proc Natl Acad Sci U S A 1973;70(8): 2281e5. [193] Gold LS, Slone TH, Ames BN. What do animal cancer tests tell us about human cancer risk? Overview of analyses of the carcinogenic potency database. Drug Metab Rev 1998;30(2):359e404. [194] Biran A, Yagur-Kroll S, Pedahzur R, et al. Bacterial genotoxicity bioreporters. Microb Biotechnol 2010; 3(4):414e27. [195] Benigni R, Bossa C, Tcheremenskaia O, et al. Alternatives to the carcinogenicity bioassay: in silico methods, and the in vitro and in vivo mutagenicity assays. Expert Opin Drug Metab Toxicol 2010;6(7):809e19.

259

[196] Mortelmans K, Zeiger E. The Ames Salmonella/microsome mutagenicity assay. Mutat Res 2000;455:29e60. [197] http://www.oecd-ilibrary.org/environment/test-no475-mammalian-bone-marrow-chromosome-aberrationtest_9789264071308-en. [198] Thun MJ, Linet MS, Cerhan JR, et al. Shottenfeld and Fraumeni: cancer epidemiology and prevention. 4th ed.. New York: Oxford University Press; 2018. p. 86. [199] International Agency for Research on Cancer (IARC): Monographs on the Identification of Carcinogenic Hazards to Humans. http://monographs.iarc.fr/ index.php. [200] http://www.iarc.fr/en/media-centre/iarcnews/pdf/ Monographs_Back_Q&A.pdf. [201] Environmental Protection Agency. Programs of the Office of the Science Advisor. Basic information about risk assessment guidelines development. Last updated 2016. http://www.epa.gov/raf/publications/pdfs/ CANCER_GUIDELINES_FINAL_3-25-05.PDF. [202] Carbone M, Pass HI. Multistep and multifactorial carcinogenesis: when does a contributing factor become a carcinogen? Semin Cancer Biol 2004;14(6): 399e405. [203] Breheny D, Zhang H, Massey ED. Application of a two-stage Syrian hamster embryo cell transformation assay to cigarette smoke particulate matter. Mutat Res 2005;572(1e2):45e57. [204] Bignold LP. Alkylating agents and DNA polymerases. Anticancer Res 2006;26(2B):1327e36. [205] Henderson L, Brusick D, Ratpan F, et al. A review of the genotoxicity of ethylbenzene. Mutat Res 2007; 635(2e3). 81-13. [206] Armstrong MJ, Gara JP, Gealy 3rd R, et al. Induction of chromosome aberrations in vitro by phenolphthalein: mechanistic studies. Mutat Res 2000;457(1e2): 15e30. [207] Leonard A, Gerber GB, Stecca C, et al. Mutagenicity, carcinogenicity, and teratogenicity of acrylonitrile. Mutat Res 1999;436(3):263e83. [208] Bomhard EM, Herbold BA. Genotoxic activities of aniline and its metabolites and their relationship to the carcinogenicity of aniline in the spleen of rats. Crit Rev Toxicol 2005;35(10):783e835. [209] Cohen SM, Arnold LL. Chemical carcinogenesis. Toxicol Sci 2011;120(Suppl. 1):S76e132. [210] Raffle AE, Muir Gray JA. Screening: evidence and practice. Oxford: Oxford University Press; 2007. [211] Henderson S, DeGroff A, Richards TB, et al. A qualitative analysis of lung cancer screening practices by primary care physicians. J Community Health 2011;36(6):949e56.

260

8. Prevention of tumors

[212] Center for Disease Control. Who should be screened for lung cancer? https://www.cdc.gov/cancer/ lung/basic_info/screening.htm. [213] Kinsinger LS, Anderson C, Kim J, et al. Implementation of lung cancer screening in the veterans health administration. JAMA Intern Med 2017;177(3): 399e406. [214] Tammemagi M, Ritchie AJ, Atkar-Khattra S, et al. Predicting malignancy risk of screen detected lung nodules e mean diameter or volume? J Thorac Oncol 2019;14(2):203e11. pii: S1556-0864(18)33187-3. [215] Nemesure B, Plank A, Reagan L, et al. Evaluating efficacy of current lung cancer screening guidelines. J Med Screen 2017;24(4):208e13. [216] Treskova M, Aumann I, Golpon H, et al. Trade-off between benefits, harms and economic efficiency of lowdose CT lung cancer screening: a microsimulation analysis of nodule management strategies in a population-based setting. BMC Med 2017;15(1):162. [217] Medical Advisory Secretariat. Fecal occult blood test for colorectal cancer screening: an evidence-based analysis. Ont Health Technol Assess Ser 2009;9(10): 1e40. [218] Lee JK, Liles EG, Bent S, et al. Accuracy of fecal immunochemical tests for colorectal cancer: systematic review and meta-analysis. Ann Intern Med 2014; 160(3):171. [219] Garborg K, Holme Ø, Løberg M, et al. Current status of screening for colorectal cancer. Ann Oncol 2013; 24(8):1963e72. [220] Holme Ø, Bretthauer M, Fretheim A, et al. Flexible sigmoidoscopy versus faecal occult blood testing for colorectal cancer screening in asymptomatic individuals. Cochrane Database Syst Rev 2013;9: CD009259. [221] Fletcher SW. Breast cancer screening: a 35-year perspective. Epidemiol Rev 2011;33(1):165e75. [222] Nelson AL. Controversies regarding mammography, breast self-examination, and clinical breast examination. Obstet Gynecol Clin North Am 2013; 40(3):413e27. [223] Naji L, Randhawa H, Sohani Z, et al. Digital rectal examination for prostate cancer screening in primary care: a systematic review and meta-analysis. Ann Fam Med 2018;16(2):149e54. [224] Justman S. How did the PSA system arise? J R Soc Med 2010;103(8):309e14. [225] Bryant RJ, Lilja H. Emerging PSA-based tests to improve screening. Urol Clin North Am 2014;41(2): 267e76. [226] Hakama M, Auvinen A. Cancer screening. In: Heggenhougen K, Quah S, editors. International

[227] [228]

[229]

[230]

[231]

[232]

[233]

[234]

[235] [236]

[237]

[238]

[239]

[240]

[241]

encyclopedia of public health. Philadelphia, PA: Elsevier; 2008. p. 470e1. Tambouret RH. The evolution of the Papanicolaou smear. Clin Obstet Gynecol 2013;56(1):3e9. Denny L. Cytological screening for cervical cancer prevention. Best Pract Res Clin Obstet Gynaecol 2012;26(2):189e96. Kamal R, Hamed S, Mansour S, et al. Ovarian cancer screening-ultrasound; impact on ovarian cancer mortality. Br J Radiol 2018;91(1090):20170571. Shellenberger R, Nabhan M, Kakaraparthi S. Melanoma screening: a plan for improving early detection. Ann Med 2016;48(3):142e8. US Preventive Services Task Force. Skin cancer: screening e recommendation. July 2016. https://www. uspreventiveservicestaskforce.org/Page/Document/ UpdateSummaryFinal/skin-cancer-screening2?. Pinheiro H, Oliveira P, Oliveira C. Hereditary cancer risk assessment: challenges for the next-gen sequencing era. Front Oncol 2015;5:62. Musolf AM, Simpson CL, de Andrade M, et al. Familial lung cancer: a brief history from the earliest work to the most recent studies. Genes 2017;8(1). pii: E36. Broderick P, Dobbins SE, Chubb D, et al. Validation of recently proposed colorectal cancer susceptibility gene variants in an analysis of families and patientsa systematic review. Gastroenterology 2017;152(1): 75e77.e4. Zetner DB, Bisgaard ML. Familial colorectal cancer type X. Curr Genomics 2017;18(4):341e59. van Marcke C, De Leener A, Berliere M, et al. Routine use of gene panel testing in hereditary breast cancer should be performed with caution. Crit Rev Oncol Hematol 2016;108:33e9. Lynch HT, Kosoko-Lasaki O, Leslie SW, et al. Screening for familial and hereditary prostate cancer. Int J Cancer 2016;138(11):2579e91. Azuaje F, editor. Bioinformatics and biomarker discovery: "Omic" data analysis for personalised medicine. Chichester, West Sussex: Wiley-Blackwell; 2010. Ulahannan D, Kovac MB, Mulholland PJ, et al. Technical and implementation issues in using nextgeneration sequencing of cancers in clinical practice. Br J Cancer 2013;109(4):827e35. National Cancer Institute: Crunching numbers: what cancer screening statistics really tell us. https:// www.cancer.gov/about-cancer/screening/research/ what-screening-statistics-mean [accessed October 2018]. Pace LE, Keating NL. A systematic assessment of benefits and risks to guide breast cancer screening decisions. J Am Med Assoc 2014;311(13):1327e35.

References

[242] Marmot MG, Altman DG, Cameron DA, et al. The benefits and harms of breast cancer screening: an independent review. Br J Cancer 2013;108(11):2205e40. [243] Croswell JM, Harris RP, Kramer BS. Cancer screening. In: Thun MJ, Linet MS, Cerhan JR, et al., editors. Shottenfeld and Fraumeni: cancer epidemiology and prevention. 4th ed.. New York: Oxford University Press; 2018. p. 1262e4. [244] Kelloff GJ, Boone CW, Malone WF, et al. Introductory remarks: development of chemopreventive agents for prostate cancer. J Cell Biochem Suppl 1992;16H:1e8. [245] Patterson SL, Colbert Maresso K, et al. Cancer chemoprevention: successes and failures. Clin Chem 2013; 59(1):94e101. [246] Lambert JD. Does tea prevent cancer? Evidence from laboratory and human intervention studies. Am J Clin Nutr 2013;98(6 Suppl. l):1667Se75S. [247] Martin MA, Goya L, Ramos S. Potential for preventive effects of cocoa and cocoa polyphenols in cancer. Food Chem Toxicol 2013;56:336e51. [248] Kelloff GJ, Hawk ET, Sigman CC, editors. Cancer chemoprevention, 2 vols.. New York, NY: Springer; 2004. 2005. [249] Miller AB, Bartsch H, Boffetta P, et al. Biomarkers in cancer chemoprevention. Lyon: IARC Scientific Publication, No 154; 2001. http://www.iarc.fr/en/ publications/pdfs-online/prev/sp154/SP154.pdf. [250] Wattenberg LW. What are the critical attributes for cancer chemopreventive agents? Ann N Y Acad Sci 1995;768:73e81. [251] Cuzick J. Preventative therapy. In: Thun MJ, Linet MS, Cerhan JR, et al., editors. Shottenfeld and Fraumeni: cancer epidemiology and prevention. 4th ed.. New York: Oxford University Press; 2018. p. 1229e37. [252] Rockhill B, Weed D. Increasing the contribution of epidemiology to the primary prevention of cancer. In: Siemiatycki J, Richardson L, Boffetta P. Occupation. Schottenfeld D, Fraumeni JF Jr (eds). Cancer epidemiology and prevention. 3rd edn, Oxford University Press, Oxford, 2006, p 1292-1302. [253] Steele VE, Lubet RA. The use of animal models for cancer chemoprevention drug development. Semin Oncol 2010;37(4):327e38. [254] Steele VE, Lubet RA, Moon RC. Preclinical animal models for the development of cancer chemoprevention drugs. In: Kelloff GJ, Hawk ET, Sigman CC (eds). Cancer Chemoprevention, Vol 2, Springer, NY, 2004, p 39-46. [255] Crowell JA. The chemopreventive agent development research program in the Division of Cancer Prevention of the US National Cancer Institute: an overview. Eur J Cancer 2005;41(13):1889e910.

261

[256] Steward WP, Brown K. Cancer chemoprevention: a rapidly evolving field. Br J Cancer 2013;109(1):1e7. [257] Szabo E, Mao JT, Lam S, et al. Chemoprevention of lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;43(5 Suppl. l):e40Se60S. [258] Lazzeroni M, DeCensi A. Breast cancer prevention by antihormones and other drugs: where do we stand? Hematol Oncol Clin North Am 2013;27(4):657e72 [vii]. [259] Cooper K, Squires H, Carroll C, et al. Chemoprevention of colorectal cancer: systematic review and economic evaluation. Health Technol Assess 2010;14(32):1e206. [260] Sandhu GS, Nepple KG, Tanagho YS, et al. Prostate cancer chemoprevention. Semin Oncol 2013;40(3): 276e85. [261] Butow P, Phillips KA. Medication to reduce breast cancer risk: why is uptake low? Ann Oncol 2016;27:553e4. [262] Thun MJ, Wild CP, Colditz G. Framework for understanding cancer prevention. In: Thun MJ, Linet MS, Cerhan JR, et al., editors. Shottenfeld and Fraumeni: cancer epidemiology and prevention. 4th ed.. New York: Oxford University Press; 2018. p. 1198. [263] https://www.osha.gov/dsg/topics/pel/. [264] Greim H, Albertini RJ, editors. The cellular response to the genotoxic insult: the question of threshold for genotoxic carcinogens. Cambridge UK: RSC Publishing; 2014. [265] Huff J. Issues and controversies surrounding qualitative strategies for identifying and forecasting cancer causing agents in the human environment. Pharmacol Toxicol 1993;72(Suppl. 1):14e27. [266] O’Brien J, Renwick AG, Constable A, et al. Approaches to the risk assessment of genotoxic carcinogens in food: a critical appraisal. Food Chem Toxicol 2006;44(10):1614e35. [267] UD Department of Labor, Occupational safety and health administration. Maximum permissible dose equivalent for occupational exposure, Ionizing radiation 1975. https://www.osha.gov/SLTC/ radiationionizing/introtoionizing/ionizingattachment six.html [268] US Department of Health and Human Services. National Institute for occupational safety and health. Update of NIOSH carcinogen classification and target risk level policy for chemical hazards in the workplace. 2013. http://www.cdc.gov/niosh/docket/review/ docket240A/pdf/EID-CIB-11052013.pdf. [269] Thomas F, Roche B, Ujvari B. Intrinsic versus extrinsic cancer risks: the debate continues. Spotlight 2016;2(2): 68e9.