Twenty-nine occupational agents, as well as 18 exposure circumstances are carcinogenic to humans It...

OCCUPATIONAL CANCER

-Ionizing Radiation-

OREN ZACK MD MOCCH

Introduction• Twenty-nine occupational agents, as well as 18 exposure circumstances are

carcinogenic to humans

• It has been known for over 200 years that exposures encountered at the workplace are a cause of cancer

• Initially detected by clinicians: Percival Pott - scrotal cancer, chimney sweeps (soot) (1771), Creech and Johnson’s – liver angiosarcoma, vinyl chloride workers (1974)

• The period of formal epidemiological assessment of the occurrence of cancer in relation to workplace exposures started after World War II. Knowledge of the occupational and other environmental causes of cancer grew rapidly in the 1950s and 1960s.

• Estimates of the burden of occupational cancer in high-resource countries are in the order of 2–5%.

Group 1: World Cancer Report, 2008

Group 2A: World Cancer Report, 2008

Introduction (cont.)

• The distinction between occupational and environmental carcinogens is not always straightforward

• Exposure levels tend to be higher at the workplace

• There are agents that have been evaluated in IARC groups 1 or 2A, for which exposure is not primarily occupational, but which often encountered in the occupational environment

• Nursing staff - cyclophosphamide, cyclosporine

• Food processors – aflatoxins

• Medical personnel – HBV, HCV, HIV

• Agriculture, fishing, outdoor occupants – solar radiation

• Public settings, bars – secondhand tobacco smoke

Introduction (cont.)

• Polycyclic aromatic hydrocarbons (PAHs) represent a specific problem in the identification of occupational carcinogens

• Includes several potent experimental carcinogens, such as benzo[a]pyrene, benz[a]anthracene and dibenz[a,h]anthracene.

• However, humans are always exposed to mixtures of PAHs and an assessment of the carcinogenicity of individual PAHs in humans is difficult

• Current understanding of the relationship between occupational exposures and cancer is far from complete; in fact, for many experimental carcinogens no definitive evidence is available from exposed workers.

• In some cases, there is considerable evidence of increased risks associated with particular industries and occupations, although no specific agents can be identified as etiological factors

• Fifteen occupations and industries are listed in IARC Group 1 and four in Group 2A

World Cancer Report, 2008

Difficulties in Establishing Causality

• Constructing and interpreting lists of chemical or physical carcinogenic agents and associating them with specific occupations and industries is complicated by a number of factors:

• Information on industrial processes and exposures is frequently poor, not allowing a complete evaluation of the importance of specific carcinogenic exposures in different occupations or industries

• Exposures to well-known carcinogenic exposures, such as vinyl chloride and benzene, occur at different intensities in different occupational situations

• Changes in exposure occur over time in a given occupational situation, either because identified carcinogenic agents are substituted by other agents or (more frequently) because new industrial processes or materials are introduced

• Any list of occupational exposures can only refer to the relatively small number of chemical exposures that have been investigated with respect to the presence of a carcinogenic risk

• A single figure on the proportion of cancers due to occupations might be misleading as exposure concentrates on subgroups of the population, namely male blue-collar workers, among whom the burden can be substantial.

Other Factors• The increasing employment of women in jobs outside the home has probably

contributed to changes in reproductive habits, which may entail an increased risk of hormone-related cancers

• Shiftwork that involves circadian disruption has been classified as a probable human carcinogen by the IARC Monographs Program, on the basis of limited evidence of an increased risk of breast cancer

• Occupational cancer is likely to be a more important problem in medium- and low-resource countries than in high-resource countries:

• Importance of the informal sector

• Lack of stringent implementation of existing regulations

• Low level of attention paid by management and the workforce to industrial hygiene

• Presence of child labor

Frequent Tumor Sites: Occupational

• Lung

• Urinary bladder

• Nasal cavity

• Liver (angiosarcoma)

• Mesothelioma

• Leukemia

• Non-melanocytic skin cancer

Carcinogenesis

• Cancer is a multi-step process during which cells undergo profound metabolic and behavioral changes, leading them to proliferate in an excessive and untimely way, to escape surveillance by the immune system, and ultimately to invade distant tissues to form metastases

Initiators and PromotersInitiators Promoters

One time exposure sufficient Repeated exposure usually necessary

No threshold There is both a threshold and a maximum effect of promoters

Carcinogenic No effect without the initiator

Bind to DNA Do not covalently bind to DNA / macromolecules

Effect irreversible Reversible effect

Mutagenic Non-mutagenic

• Examples:

• PAH

• Tobacco smoke

• Diethyl-nitrosamine

• Methylnitrosurea

• 2-naphthylamine

• 2-Acetylaminofluoren

e

• Examples:

• Croton oil

• Tobacco smoke

• DDT, PCBs

• Saccharin

• D, L Tryptophan

• Phenobarbital

Oncogenes and TSGs

International Agency for Research on Cancer (IARC)

Monograph Program• The International Agency for Research on Cancer was established in May, 1965

• Monograph program is functioning since 1971

• More than 900 agents have been evaluated, of which more than 400 have been identified as carcinogenic, probably carcinogenic, or possibly carcinogenic to humans

• Objective: identifying environmental factors that can increase the risk of human cancer

Agents Classified by the IARC Monographs, Volumes 1-108

Group Classification Number of agents classified

Group 1 The agent, mixture, or exposure circumstance is carcinogenic to humans 111

Group 2A The agent, mixture, or exposure circumstance is probably carcinogenic to humans 66

Group 2B The agent, mixture, or exposure circumstance is possibly carcinogenic to humans 285

Group 3 The agent, mixture, or exposure circumstance is not classifiable as to its carcinogenicity to humans 505

Group 4 The agent, mixture, or exposure circumstance is probably not carcinogenic to humans 1

IARC Classification• Evaluations of the epidemiological and experimental evidence of the carcinogenicity

are performed for chemicals, complex mixtures, occupational exposures, physical and biological agents, and lifestyle factors.

• Agents are selected by the IARC to be evaluated if there is evidence that exposure occurs in humans, and also if there is suspicion that the agent could cause cancer.

• The evidence used in the IARC monographs is based on

• Exposure data

• Epidemiological studies

• Studies in experimental animals

• Data on mechanisms of action (e.g. kinetics, mutagenicity)

IARC Classification (cont.)

• The IARC does not categorize the carcinogens evaluated as for the source of exposure and therefore does not indicate which should be considered as occupational.

• To identify which carcinogens could be classified as occupational, it is necessary to review the text of the monographs and then apply ad hoc criteria.

• The identification and listing of exposures that could be defined as occupational can be complex. Many occupational exposures also occur in the general environment and, vice versa, many predominantly environmental exposures occur in the occupational environment.

Carcinogenicity in Humans• Sufficient evidence of carcinogenicity

• A causal relationship has been established between exposure to the agent and human cancer. That is, a positive relationship has been observed between the exposure and cancer in studies in which chance, bias and confounding could be ruled out with reasonable confidence

• Limited evidence of carcinogenicity

• A positive association has been observed, but chance, bias or confounding could not be ruled out with reasonable confidence

• Inadequate evidence of carcinogenicity

• Available studies are of insufficient quality, consistency or statistical power to permit a conclusion regarding the presence or absence of a causal association between exposure and cancer, or no data on cancer in humans are available

• Evidence suggesting lack of carcinogenicity

• Several adequate studies covering the full range of levels of exposure that humans are known to encounter, which are mutually consistent in not showing a positive association between exposure to the agent and any studied cancer at any observed level of exposure

Carcinogenicity in Experimental Animals

• Sufficient evidence of carcinogenicity

• A causal relationship has been established between the agent and an increased incidence of malignant neoplasms or of an appropriate combination of benign and malignant neoplasms in (a) two or more species of animals or (b) two or more independent studies in one species carried out at different times or in different laboratories or under different protocols

• An increased incidence of tumors in both sexes of a single species in a well-conducted study, ideally conducted under Good Laboratory Practices, can also provide sufficient evidence

• A single study in one species and sex might be considered to provide sufficient evidence of carcinogenicity when malignant neoplasms occur to an unusual degree with regard to incidence, site, type of tumor or age at onset, or when there are strong findings of tumors at multiple sites

• Limited evidence of carcinogenicity

• (a) the evidence of carcinogenicity is restricted to a single experiment;

• (b) there are unresolved questions regarding the adequacy of the design, conduct or interpretation of the studies;

• (c) the agent increases the incidence only of benign neoplasms or lesions of uncertain neoplastic potential; or

• (d) the evidence of carcinogenicity is restricted to studies that demonstrate only promoting activity in a narrow range of tissues or organs

Carcinogenicity in Experimental Animals

• Inadequate evidence of carcinogenicity

• Evidence suggesting lack of carcinogenicity• Studies involving at least two species are available which show that,

within the limits of the tests used, the agent is not carcinogenic

• A conclusion of evidence suggesting lack of carcinogenicity is inevitably limited to the species, tumour sites, age at exposure, and conditions and levels of exposure studied

Mechanistic and Other Relevant Data

• Data on preneoplastic lesions, tumor pathology, genetic and related effects, structure-activity relationships, metabolism and toxicokinetics, physicochemical parameters and analogous biological agents

• Strength of evidence: weak, moderate or strong

• Working Group assesses whether the particular mechanism is likely to be operative in humans

• Data may be considered to be especially relevant if they show that the agent in question has caused changes in exposed humans that are on the causal pathway to carcinogenesis

• The conclusion that a mechanism operates in experimental animals is strengthened by findings of consistent results in different experimental systems, by the demonstration of biological plausibility and by coherence of the overall database

• Multiple mechanisms might contribute to tumor development

• Different mechanisms might operate in different dose ranges

• Separate mechanisms might operate in humans and experimental animals

• A unique mechanism might operate in a susceptible group

Other evidence Animal evidence Epidemiological evidence

Group

Any Any Sufficient 1 – Carcinogenic to humansRelevant

mechanismSufficient Less than

sufficientAny Sufficient Limited 2A – probably


Exceptionally:

Relevant mechanism

Sufficient Inadequate

LimitedAny Less than

sufficientLimited 2B – possibly


Exceptionally:

Sufficient InadequateRelevant mechanism

Less than sufficient

Inadequate

Strong mechanistic Limited /

inadequateInadequate 3 – not classifiable

as carcinogenic to humansMechanistic

againstSufficient Inadequate

Any Suggesting lack of carcinogenicity

Suggesting lack of carcinogenicity

4 – probably not carcinogenic to humans

Strongly negative mechanistic

Suggesting lack of carcinogenicity

Inadequate

Group 1 Agents, Volumes 1-108Agent Group Volume Year

Acetaldehyde associated with consumption of alcoholic beverages 1 100E 2012

Acid mists, strong inorganic 1 54, 100F 2012

Aflatoxins 1 56, 82, 100E 2012

Alcoholic beverages 1 44, 96, 100E 2012

Aluminum production 1 34, Sup 7, 100F 2012

4-Aminobiphenyl1

1, Sup 7, 99, 100F

2012

Areca nut 1 85, 100E 2012

Aristolochic acid(NB: Overall evaluation upgraded to Group 1 based on mechanistic and other relevant data)

1 82, 100A 2012

Aristolochic acid, plants containing 1 82, 100A 2012

Arsenic and inorganic arsenic compounds 1 23, Sup 7, 100C 2012

Asbestos (all forms, including actinolite, amosite, anthophyllite, chrysotile, crocidolite, tremolite)(NB: Mineral substances (e.g. talc or vermiculite) that contain asbestos should also be regarded as carcinogenic to humans.)

1 14, Sup 7, 100C 2012


Auramine production 1 Sup 7, 99, 100F 2012

Azathioprine 1 26, Sup 7, 100A 2012

Benzene 1 29, Sup 7. 100F 2012

Benzidine1

29, Sup 7, 99, 100F

2012

Benzidine, dyes metabolized to(NB: Overall evaluation upgraded to Group 1 based on mechanistic and other relevant data)

1 99, 100F 2012

Benzo[a]pyrene(NB: Overall evaluation upgraded to Group 1 based onmechanistic and other relevant data)

1 92, 100F 2012

Beryllium and beryllium compounds 1 58, 100C 2012

Betel quid with tobacco 1 85, 100E 2012

Betel quid without tobacco 1 85, 100E 2012

Bis(chloromethyl)ether; chloromethyl methyl ether (technical-grade) 1 4, Sup 7, 100F 2012

Busulfan 1 4, Sup 7, 100A 2012

1,3-Butadiene 1 97, 100F 2012


Cadmium and cadmium compounds 1 58, 100C 2012

Chlorambucil 1 26, Sup 7, 100A 2012

Chlornaphazine 1 4, Sup 7, 100A 2012

Chromium (VI) compounds 1 49, 100C 2012

Clonorchis sinensis (infection with) 1 61, 100B 2012

Coal, indoor emissions from household combustion of 1 95, 100E 2012

Coal gasification 1 92, 100F 2012

Coal-tar distillation 1 92, 100F 2012

Coal-tar pitch 1 35, Sup 7, 100F 2012

Coke production 1 92, 100F 2012

Cyclophosphamide 1 26, Sup 7, 100A 2012

Cyclosporine 1 50, 100A 2012

Diethylstilbestrol 1 21, Sup 7, 100A 2012

Engine exhaust, diesel 1 46, 105 In prep


Epstein-Barr virus 1 70, 100B 2012

Erionite 1 42, Sup 7, 100C 2012

Estrogen therapy, postmenopausal 1 72, 100A 2012

Estrogen-progestogen menopausal therapy (combined) 1 72, 91, 100A 2012

Estrogen-progestogen oral contraceptives (combined)(NB: There is also convincing evidence in humans that these agents confer a protective effect against cancer in the endometrium and ovary)

1 72, 91, 100A 2012

Ethanol in alcoholic beverages 1 96, 100E 2012

Ethylene oxide(NB: Overall evaluation upgraded to Group 1 based on mechanistic and other relevant data)

1 97, 100F 2012

Etoposide(NB: Overall evaluation upgraded to Group 1 based on mechanistic and other relevant data)

1 76, 100A 2012

Etoposide in combination with cisplatin and bleomycin 1 76, 100A 2012

Fission products, including strontium-90 1 100D 2012

Formaldehyde 1 88, 100F 2012

Haematite mining (underground) 1 1, Sup 7, 100D 2012


Helicobacter pylori (infection with) 1 61, 100B 2012

Hepatitis B virus (chronic infection with) 1 59, 100B 2012

Hepatitis C virus (chronic infection with) 1 59, 100B 2012

Human immunodeficiency virus type 1 (infection with) 1 67, 100B 2012

Human papillomavirus types 16, 18, 31, 33, 35, 39, 45,51, 52, 56, 58, 59(NB: The HPV types that have been classified as carcinogenic to humans can differ by an order of magnitude in risk for cervical cancer)

1 64, 90, 100B 2012

Human T-cell lymphotropic virus type I 1 67, 100B 2012

Ionizing radiation (all types) 1 100D 2012

Iron and steel founding (occupational exposure during) 1 34, Sup 7, 100F 2012

Isopropyl alcohol manufacture using strong acids 1 Sup 7, 100F 2012

Kaposi sarcoma herpesvirus 1 70, 100B 2012

Leather dust 1 100C 2012

Magenta production 1 57, 99, 100F 2012

Melphalan 1 9, Sup 7, 100A 2012


Methoxsalen (8-methoxypsoralen) plus ultraviolet A radiation 1 24, Sup 7, 100A 2012

4,4'-Methylenebis(2-chloroaniline) (MOCA)(NB: Overall evaluation upgraded to Group 1 based on mechanistic and other relevant data)

1 57, 99, 100F 2012

Mineral oils, untreated or mildly treated 1 33, Sup 7, 100F 2012

MOPP and other combined chemotherapy including alkylating agents

1 Sup 7, 100A 2012

2-Naphthylamine1

4, Sup 7, 99, 100F

2012

Neutron radiation(NB: Overall evaluation upgraded to Group 1 with supporting evidence from other relevant data)

1 75, 100D 2012

Nickel compounds 1 49, 100C 2012

N'-Nitrosonornicotine (NNN) and 4-(NNitrosomethylamino)-1-(3-pyridyl)-1-butanone (NNK)(NB: Overall evaluation upgraded to Group 1 based on mechanistic and other relevant data)

1 89, 100E 2012

Opisthorchis viverrini (infection with) 1 61, 100B 2012

Painter (occupational exposure as a) 1 79, 98, 100F 2012

3,4,5,3’,4’-Pentachlorobiphenyl (PCB-126)(see Polychlorinated biphenyls, dioxin-like, with a TEF according to WHO)

1 100F 2012


2,3,4,7,8-Pentachlorodibenzofuran(NB: Overall evaluation upgraded to Group 1 based on mechanistic and other relevant data)

1 100F 2012

Phenacetin(NB: Overall evaluation upgraded to Group 1 with supporting evidence from other relevant data)

1 24, Sup 7, 100A 2012

Phenacetin, analgesic mixtures containing 1 Sup 7, 100A 2012

Phosphorus-32, as phosphate 1 78, 100D 2012

Plutonium 1 78, 100D 2012

Polychlorinated biphenyls 1 18, Sup 7, 107 In prep

Polychlorinated biphenyls, dioxin-like, with a Toxicity Equivalency Factor (TEF) according to WHO (PCBs 77, 81, 105, 114, 118, 123, 126, 156, 157, 167, 169, 189)(NB: Overall evaluation upgraded to Group 1 with strong supporting evidence from other relevant data)

1 107 In prep

Radioiodines, including iodine-131 1 78, 100D 2012

Radionuclides, alpha-particle-emitting, internally deposited(NB: Specific radionuclides for which there is sufficient evidence in humans are also listed individually as Group 1 agents)

1 78, 100D 2012


Radionuclides, beta-particle-emitting, internally deposited (NB: Specific radionuclides for which there is sufficient evidence in humans are also listed individually as Group 1 agents)

1 78, 100D 2012

Radium-224 and its decay products 1 78, 100D 2012



Radon-222 and its decay products 1 78, 100D 2012

Rubber manufacturing industry 1 28, Sup 7, 100F 2012

Salted fish, Chinese-style 1 56, 100E 2012

Schistosoma haematobium (infection with) 1 61, 100B 2012

Semustine [1-(2-Chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea, Methyl-CCNU]

1 Sup 7, 100A 2012

Shale oils 1 35, Sup 7, 100F 2012

Silica dust, crystalline, in the form of quartz or cristobalite 1 68, 100C 2012

Solar radiation 1 55, 100D 2012

Soot (as found in occupational exposure of chimney sweeps) 1 35, Sup 7, 100F 2012

Sulfur mustard 1 9, Sup 7, 100F 2012

Group 1 Agents, Volumes 1-108

Agent Group Volume YearTamoxifen(NB: There is also conclusive evidence that tamoxifen reduces the risk of contralateral breast cancer in breast cancer patients)

1 66, 100A 2012

2,3,7,8-Tetrachlorodibenzo-para-dioxin 1 69, 100F 2012

Thiotepa 1 50, 100A 2012

Thorium-232 and its decay products 1 78, 100D 2012

Tobacco, smokeless 1 89, 100E 2012

Tobacco smoke, second-hand 1 83, 100E 2012

Tobacco smoking 1 83, 100E 2012

ortho-Toluidine 1 77, 99, 100F 2012

Treosulfan 1 26, Sup 7, 100A 2012

Trichloroethylene 1 63, 106 In prep

Ultraviolet radiation (wavelengths 100-400 nm, encompassing UVA, UVB, and UVC)

1 100D 2012

Ultraviolet-emitting tanning devices 1 100D 2012

Vinyl chloride 1 97, 100F 2012

Wood dust 1 62, 100C 2012

X- and Gamma-Radiation 1 75, 100D 2012

Selected Group 2 & 3 Agents

• Group 2A

• Acrylamide

• Hairdresser as a barber

• Lead - inorganic

• Shiftwork that involves circadian disruption

• Group 2B

• Aloe vera, whole leaf extract

• Coffee (urinary bladder)

• DDT

• Dry cleaning

• Fire fighter

• ELF – magnetic fields

• RF – electromagnetic fields

• Pickled vegetables (traditional in Asia)

• Group 3

• Polystyrene

• Caffeine

• Chromium (III)

• ELF – electric fields

• Lead – organic

• Polyethylene

• PVC

• …

Common Exposures, EU

formaldehyde

ethylene dibromide

asbestos

benzene

Lead and lead compounds, inorganic

Wood dust

Radon and its decay products

Diesel engine exhaust

Silica, crystalline

Environmental tobacco smoke

Solar radiation

0 1000000 2000000 3000000 4000000 5000000 6000000 7000000 8000000 9000000

Exposures by Agents

Data: CAREX, 2010, http://www.ttl.fi/en/chemical_safety/carex/countries/pages/default.aspx

Diagnosis Considerations• Occupation accounts for all or part of the tumor process in 5 per cent of cancers

• Long latency-induction times for cancer

• As a general rule, cancers that are of occupational origin are not distinguishable from non-occupational cancers whether in clinical features, natural history, pathological findings or other special investigations

• Occupational cancer may present earlier than the non-occupational varieties

• Movement of workers between jobs, work areas or industries

• Rare tumors may be an indicator

• Multiple exposures

• Diversity of chemical nomenclature

• Confounding risk factors

Ionizing Radiation & Cancer

Stochastic Effects• Carcinogenesis

• The cancers induced by radiation, with or without the contributions of other agents, are indistinguishable from those occurring ‘spontaneously’ or from other causes

• Studies on Hiroshima and Nagasaki, radium exposed employees in luminizing industry, miners exposed to radon, Chernobyl survivors

• The cancer risks derived from such exposed groups are influenced largely by exposures to high doses, which were delivered over a short period of time. In practice, most people are exposed occupationally to low doses of radiation received over relatively long periods

• The risk factor or lifetime fatality probability coefficient from ICRP for a reference population of both sexes and of working age is 4.1 × 10−2/Sv for the sum of all fatal malignancies, i.e. A dose of 1Sv in a working lifetime results in a 4 per cent chance of a fatal cancer occurring

Sources of Information• Most of the information on radiation-induced cancer risk comes from

• (a) Japanese atomic bomb survivors (Life Span Study)

• Both genders, a wide range of ages comparable with those of a general population

• (b) Medically exposed populations

• More restricted age and gender mix

• Organ doses among those treated with radiotherapy tend to be higher than those received by the A-bomb survivors

• (c) Occupationally exposed groups

• More restricted in their age and gender mix. For example: cohorts of workers exposed in the nuclear industry are overwhelmingly male and exposed in adulthood

• For these reasons, most standard setting bodies use the LSS as the basis for estimates of population cancer risk associated with exposure to low LET radiation

Dose-Response Models• Linear no-threshold model (LNT)

• Consistent excess risk with increasing exposure dose

• Additive effect

• Applicable to high-let

• Most reasonable description of the relation between low-dose exposure to IR and the incidence of solid cancers

• Linear-quadratic model

• Linear increase in low doses

• Exponential increase in high doses

• Applicable to low-let

• Best-suited for leukemia

• Threshold model

• A threshold exist below which no excess risk is seen

• Cannot be ruled out at low doses, given cellular repair mechanisms and judging from epidemiological data

Risk Models

In a lifetime, approximately 42 (solid circles) of 100 people will be diagnosed with cancer.

Calculations suggest that approximately one cancer (solid red) per 100 people could result from a single exposure to 0.1 Sv of low-LET radiation above background

Low-dose, low-LET radiation

Stochastic Effects• Probability of causation

• The question: if a person has been exposed to ionizing radiation and subsequently develops a cancer, what is the probability that the cancer was due to the earlier exposure

• Probability =

• ERR varies in direct proportion to the dose

• ERR can be affected by

• Sex

• Age at exposure

• Time between exposure and illness

• Degree of dose protraction

Excess relative riskThe ratio of the excess risk of a specified

stochastic effect to the probability of the same effect in the unexposed population.

In theory, this should be equal to the attributable risk from the exposure received by the exposed group, but ERR is normally used in

the context of observed numbers of effects, whereas AR normally refers to a figure

calculated on the basis of a known or estimated exposure

IARC, 2000-2001• X-radiation and γ-radiation were previously classified as Group 1 carcinogens

• Classification was based on increased risk of several cancers associated with X- and γ-

rays, including:

• Leukemia (excluding chronic lymphocytic leukemia),

• Breast cancer in women exposed before the menopause,

• Cancer of the thyroid gland among people exposed during childhood,

• Non-melanoma skin cancer,

• Cancer of the stomach,

• Cancer of the colon, and

• Cancer of the lung

X- and γ- Radiations

Detonation of Atomic Bombs

Leukemia• Evidence of excess risk of leukemia among A-bomb survivors

• Increased risk with increasing magnitude of dose

• Largest excess risks observed for those exposed at younger ages

• Excess tended to diminish in magnitude with time since exposure

• The exposure–response relationship appeared to be linear-quadratic

• ERR/Gy for acute myeloid leukemia was best described by a quadratic dose–response function that peaked approximately 10 years after exposure

• Mortality associated with acute lymphocytic leukemia or chronic myeloid leukemia was best described by a linear dose–response function that did not vary with time since exposure

Solid Cancers• The excess risk appeared to be linear in dose, with modifying effects of gender, age at

exposure, and attained age

• Significant radiation-associated increases in incidence were reported for cancer of the oral cavity, esophagus, stomach, colon, liver, lung, non-melanoma skin, breast, ovary, bladder, nervous system, and thyroid

Fallout from Nuclear Weapon Testing

• A significant trend with dose was observed for cancer of:

• The stomach (ERR/Sv, 1.68; 95%CI: 0.83–2.99),

• Lung (ERR/Sv, 2.60; 95%CI: 1.38–4.63), and of

• The female breast (ERR/Sv, 1.28; 95%CI: 0.27–3.28)

• However, selection bias regarding the comparison group could not be ruled out.

• Based on the data for the exposed group only, the estimate of the ERR/Sv for

• All solid tumors was 0.81 (95%CI: 0.46–1.33); for

• Cancer of the stomach, 0.95 (95%CI: 0.17–3.49);

• Lung, 1.76 (95%CI: 0.48–8.83), and of

• the female breast, 1.09 (95%CI:−0.05–15.8)

Medical Exposures

Lung Cancer• International Hodgkin disease study - ERR/Gy of 0.15 (95%CI: 0.06–0.39) after adjusting

for chemotherapy and smoking

• As with all studies considered, a potential problem with this study is ascertainment and adjustment for cigarette smoking. Although the methods used in this study are thorough, they are based on data abstracted from medical records, in which assessment of smoking before the primary cancer was mainly retrospective, so recall bias cannot be excluded

• Interactions

• Radiation + chemotherapy – additive

• Radiation + smoking – multiplicative

Female Breast Cancer• International Hodgkin disease study – ERR/Gy was 0.15 (95%CI: 0.04–0.73)

• Netherlands Hodgkin disease study – 0.06 (95%CI: 0.01–0.13)

• French-United Kingdom childhood cancer study – 0.13 (95%CI: < 0.0–0.75)

• US scoliosis cohorts – ERR/Gy, 2.86; 95%CI: −0.07–8.62

• The excess risk in the first three of these studies are reasonably consistent, at least for those women not treated with chemotherapy

• A complication in some of these radiotherapy studies is radiation dose to the ovaries - women receiving large ovarian doses (> 5 Gy) were at lower risk of radiation-induced breast cancer, presumably because of ovarian ablation and induced menopause

Brain (CNS) Cancer• Israeli tinea capitis study - ERR/Gy was 4.63 (95%CI: 2.43–9.12) for benign meningioma

and 1.98 (95%CI: 0.73–4.69) for malignant brain tumor

• International Childhood Cancer Study - ERR/Gy was 0.33 (95%CI: 0.07–1.71) for gliomas, 1.06 (95%CI: 0.21–8.15) for meningiomas, and 0.69 (95%CI: 0.25–2.23) for all central nervous system tumors

• In both studies, there is a pattern of increased relative risk per unit dose for benign brain tumors compared with malignant brain tumors, a pattern also observed in some other earlier studies

Leukemia• International nested case–control study on testicular cancer survivors - ERR at 10 Gy

was 3.27 (95%CI: 1.2–13)

• New York tinea capitis cohort - the standardized incidence ratio (SIR) for leukemia (following an average dose of about 4 Gy to cranial marrow) was 3.2 (95%CI: 1.5–6.1)

• No dose–response analysis was reported

Occupational Studies

IARC 15-Country Study• A collaborative study of cancer risk among workers in the nuclear industry.

• Analyses included 407,391 nuclear industry workers who were individually monitored for external irradiation and were employed in the industry for at least 1 year

• Workers with potential for substantial doses from other radiation types and workers with potential for high-dose rate exposure were excluded from the main study population

• There was limited information available on confounders, such as cigarette smoking

• Among the cancer categories examined, a significant positive dose–response association was reported for lung cancer mortality (no other specific cancer category exhibited a statistically significant dose–response trend)

• The ERR/Sv was

• 1.86 (90%CI: 0.49–3.63) for cancer of the lung,

• 1.93 (90%CI: < 0–7.14) for leukaemia (excluding chronic lymphocytic leukemia),

• 0.97 (90%CI: 0.27–1.80) for all cancers excluding leukemia,

• 0.59 (90%CI:−0.16–1.51) for all cancers excluding leukemia, lung and pleura,

• 0.87 (90%CI: 0.16–1.71) for all solid cancers

IARC 15-Country Study• The ERR/Sv was greater for those exposed at ages over 50 years than for those exposed at

younger ages.

• ERR/Sv by age at exposure was:

• All cancers excluding leukemia

• 1.74 (90%CI: 0.24–3.58) for age > 50 years,

• 1.32 (90%CI: 0.12–2.71) for age 35–50 years,

• −1.07 (90%CI: < 0–1.24) for age < 35 years.

• Cancer of the lung

• 3.87 (90%CI: 0.92–7.93) for age > 50 years,

• 1.52 (90%CI:−0.71–4.36) for age 35-50 years,

• 2.51 (90%CI:−1.96–8.89) for age < 35 years.

• Leukemia excluding CLL

• 5.01 (90%CI:< 0–14.7) for age > 50 years,

• −1.59 (90%CI: < 0–3.02) for age 35-50 years,

• 1.51 (90%CI: < 0–11.6) for age < 35 years.

IARC 15-Country Study• An analysis examined the association between radiation dose and chronic lymphocytic

leukemia mortality among 295963 workers in the seven countries with chronic lymphocytic leukemia deaths

• The relative risk (RR) at an occupational dose of 100 mSv compared to 0 mSv was 0.84 (95%CI: 0.39–1.48) under the assumption of a 10-year exposure lag

• The Working Group noted that this study had little power due to low doses (average cumulative bone marrow dose, 15 mSv), short follow-up periods, and uncertainties in chronic lymphocytic leukemia ascertainment from death certificates

UK Radiation Workers• 174,541 people occupationally exposed to ionizing radiation based on the National Registry for Radiation Workers

• Doses from the internal deposition of radionuclides were not generally available and were not used in the analysis, nor was individual information available on smoking history

• The analyses focused on doses from penetrating radiation at the surface of the body, estimated using personal dosimeters

• There was a highly significant negative association observed between mortality from bronchitis, emphysema and chronic obstructive disease and dose (ERR/Sv, −1.04; 90%CI: −1.35, −0.59)

• There was a positive association between radiation dose and mortality due to leukemia excluding chronic lymphocytic leukemia (ERR/Sv, 1.71; 90%CI: 0.06–4.29), and also between radiation dose and mortality due to all malignant neoplasms excluding leukemia (ERR/Sv, 0.28; 90%CI: 0.02–0.56)

• In analyses of cancer incidence, positive associations were also seen with leukemia excluding chronic lymphocytic leukemia (ERR/Sv, 1.78; 90%CI: 0.17–4.36), and all malignant neoplasms excluding leukemia (ERR/Sv, 0.27; 90%CI: 0.04–0.51).

• The strongest evidence of association was for CML; no association between CLL (mortality or incidence) and radiation

US Radiation Workers• A large cohort of US nuclear weapons workers at the Savannah River site reported a positive association between

leukemia mortality and radiation dose under a 3-year lag assumption (ERR/Sv, 4; 90%CI: 0–12)

• The association was of larger magnitude for leukemia excluding chronic lymphocytic leukemia (ERR/Sv, 8; 90%CI: 1–20) and for myeloid leukemia (ERR/Sv, 12; 90%CI: 2–35), and these associations tended to diminish in magnitude with time since exposure to radiation

• A positive association was also observed between lymphoma mortality and radiation dose under a 5- and 10-year lag (ERR/Sv, 6.99; 90%CI: 0.96–18.39 and ERR/Sv, 8.18; 90%CI: 1.44–21.16, respectively

• A nested case–control study of leukemia among workers at four US nuclear weapons facilities and the Portsmouth naval shipyard reported a positive [but highly imprecise] association between leukemia mortality and radiation dose (ERR/Sv, 1.44; 90%CI: <−1.03–7.59

• A case–control study of lung cancer among workers at Portsmouth Naval shipyard reported some evidence of a positive association with lung cancer, which was substantially attenuated after adjusting for medical X-ray exposures

US Radiation Workers• Analyses of leukemia, lympho-hematopoietic cancers, lung cancer, and mesothelioma among workers

from shipyards involved in nuclear powered ship overhauls

• Included 28000 workers with cumulative doses of 5 mSv or more, 10462 workers with cumulative doses less than 5 mSv, and 33353 non-nuclear workers

• Exposures were almost exclusively due to γ-radiation

• Evidence of dose-related increases in leukemia, lung cancer, and lympho-hematopoietic cancers

• In an internal comparison of workers with 50.0 mSv exposures to workers with exposures of 5.0–9.9 mSv, the relative risk was 2.41 (95%CI: 0.5–23.8) for leukaemia, 1.26 (95%CI: 0.9–1.9) for lung cancer, and 2.94 (95%CI: 1.0–12.0) for lympho-hematopoietic cancers

• The smoking habits of all individuals in the study were not available

Mayak• Exposures at Mayak included external γ-radiation exposure as well as internal α-particle exposure and

plutonium exposures

• Cohort of 21790 Mayak workers

• Average cumulative external radiation dose among those monitored for radiation was 0.8 Gy

• For external doses, the ERR/Gy was 0.17 (95%CI: 0.052–0.32) among men and 0.32 (95%CI: < 0–1.3) among women

• The potential confounding by smoking was investigated in a subset of the cohort, in which there was sparse data but the ERR/Gy was smaller when adjusted for smoking status (ERR/Gy, 0.027; 95%CI: < 0–0.18)

• The ERR/Sv (adjusted for plutonium exposure) was 0.15 (90%CI: 0.09–0.20) for solid tumors and 0.99 (90%CI: 0.45–2.12) for leukemia excluding chronic lymphocytic leukemia

Chernobyl clean-up workers• Analyses included 70 cases (40 leukemia, 20 NHL, and 10 other types) and 287 age-

matched controls

• The overall ERR/Gy was 6.0 (90%CI: −0.2, 23.5)

• The dose–response relationship was of larger magnitude for non-Hodgkin lymphoma (ERR/Gy, 28.1; 90%CI: 0.9–243.0) than for leukemia (ERR/Gy, 4.8; 90%CI: < 0, 33.1), although the confidence intervals were wide for both outcomes

• The ERR/Gy for leukemia excluding chronic lymphocytic leukemia was 5.0 (90%CI: −0.38, 5.7) based on 19 cases and 83 controls

• The risk estimate for CLL (ERR/Gy, 4.7; 90%CI: –∞, 76.1) was similar to the estimate for all leukemia combined (ERR/Gy, 4.8; 90%CI: –∞, 33.1)

Chernobyl clean-up workers• A nested case–control study of leukemia in a cohort of clean-up workers identified from

the Chernobyl State Registry of Ukraine

• 71 cases of leukemia diagnosed during 1986–2000, and 501 age- and residence-matched controls

• The ERR/Gy of total leukemia was 3.44 (95%CI: 0.47–9.78)

• Overall, the dose–response relationship for both CLL (ERR/Gy, 4.09; 95%CI: < 0–14.41) and non-CLL (ERR/Gy, 2.73; 95%CI: < 0–13.50) was comparable

• In another study the ERR/Gy of death from malignant neoplasm was 2.11 (95%CI: 1.31–2.92)

• The ERR estimation for incident solid cancers was positive [but imprecise] (ERR/Gy, 0.34; 95%CI: −0.39–1.22)

Environmental Exposures

Techa River• Exposures to γ- and β-radiation released into the Techa river, southern Urals, the Russian Federation, as a

result of operations at the Mayak production facility

• External exposures - primarily d/t contamination of shoreline and floodplains

• Internal exposures - consumption of food and drink contaminated with radionuclides

• A study on 17433 people who resided in villages along the Techa river, with follow-up from 1956–2002

• There was a highly significant linear dose–response relationship between cumulative stomach dose and incidence of solid tumors (p=0.004)

• A cohort of 9908 women with follow-up from 1956–2004

• A significant dose–response relationship (p=0.01) was reported between cumulative stomach dose and breast cancer incidence, with an estimated ERR/Gy of 5.00 (95%CI: 0.80–12.76)

• Another study of 83 cases ascertained over a 47-year period of follow-up and 415 controls

• In analyses of leukemia excluding CLL, the OR at 1 Gy, was 4.6 (95%CI: 1.7–12.3), 7.2 (95%CI: 1.7–30.0), and 5.4 (95%CI: 1.1–27.2) for total, external and internal red bone-marrow doses, respectively

High Background Radiation• Cancer risks in a cohort of Chinese residents in Taiwan, China, who received protracted low-

dose-rate γ-radiation exposures from 60Co-contaminated reinforcing steel used to build their apartments

• 117 cancer cases diagnosed during 1983–2005 among 6242 people with an average excess cumulative exposure estimate of about 48 mGy

• There was a significant association between the estimated radiation dose and leukemia excluding CLL (HR/100 mGy, 1.19; 90%CI: 1.01–1.31); the HR/100 mGy estimated for breast cancer was 1.12 (90%CI: 0.99–1.21)

• Cancer incidence in Kerala, India, in an area known for high-background radiation from thorium containing monazite sand

• A cohort of 69958 residents aged 30–84 years was ascertained through to 2005 (average duration of follow-up, 10.5 years)

• Cumulative radiation dose for each individual was estimated based on outdoor and indoor dosimetry of each household (median outdoor radiation levels were approximately 4 mGy per year)

• Analysis included 1379 cancer cases and 30 leukemia cases - found no cancer site was significantly related to cumulative radiation dose.

• The estimated ERR/Gy of cancer excluding leukemia was −0.13 (95%CI: −0.58–0.46).

Final Evaluation: X and γCancer sites and tumors judged to have sufficient evidence for a

causal association with X-ray and γ-ray exposure

Neutron Radiation

Cancer in Humans• Studies of human exposures to neutron radiation are extremely limited

• The major group is the atomic bomb (A-bomb) survivors who were exposed to fission neutrons

• The neutron component of dose is too small to make conclusions about neutron effects and relative biological effectiveness (RBE) estimates

• Occupational studies have been carried out on airline crews because of their exposure to neutrons from cosmic rays during high-altitude flights

• Increases in breast cancer and melanoma have been observed, but not leukemia

• confounding factors include circadian rhythm disruption, which may increase the risk of endocrine tumors, as well as UV exposures and the risk for melanoma

• There is not a clear cause and effect relationship between any site-specific cancer risk and employment as a pilot or flight attendant

Cancer in Humans• Nuclear workers are occasionally exposed to neutrons, but their numbers are small,

and they typically will also be exposed to higher doses of γ-radiation

• Studies of patients treated with neutrons are limited and difficult to evaluate due to the small numbers of survivors and the complex dosimetry often combined with X-rays and chemotherapy agents

• A study on fast-neutron therapy for various cancers among 620 patients in Scotland and UK - 3 cases of sarcomas were reported, which was 111 times the expected in the Scottish population

• A US study on 484 cancer patients who received neutron therapy reported poor patient survival; only 5% of cases survived 10 years or more - Nearly 50% of the study patients were treated for cancer of the uterine cervix, prostate, or head and neck

Final Evaluation: Neutrons• There is inadequate evidence in humans for the carcinogenicity of neutron radiation

• There is sufficient evidence in experimental animals for the carcinogenicity of neutron radiation

• Neutron radiation is carcinogenic to humans (Group 1) - the working group took into account:

• Every relevant biological effect of X- or γ-radiation that has been examined has been found to be induced by neutrons, including neoplastic cell transformation, mutations in vitro, germ-cell mutations in vivo, chromosomal aberrations in vivo and in vitro, and cancer in experimental animals

• Structural chromosomal aberrations (including rings, dicentrics and acentric fragments) and numerical chromosomal aberrations are induced in the lymphocytes of people exposed to neutrons

Internalized α-particle Emitting

Radionuclides

Cancer in Humans• Radon

• α-Particle emitters

• Radium-224/226/228

• Mixed α-particle emitters

• Thorium-232.

• Plutonium

• Uranium

Evaluation: α-Emitting Radionuclides

• There is sufficient evidence in humans for the carcinogenicity of radon-222 and its decay products

• Radon-222 and its decay products cause cancer of the lung

• Also, a positive association has been observed between exposure to radon-222 and leukemia

• There is sufficient evidence in humans for the carcinogenicity of underground hematite mining with exposure to radon

• Underground hematite mining with exposure to radon causes cancer of the lung

• There is sufficient evidence in humans for the carcinogenicity of radium-224

• Radium-224 causes bone sarcomas


• Radium-226 causes bone sarcomas and carcinomas of the paranasal sinuses and mastoid process


• Radium-228 causes bone sarcomas

Evaluation: α-Emitting Radionuclides

• There is sufficient evidence in humans for the carcinogenicity of thorium-232 as stabilized thorium-232 dioxide in colloidal form (Thorotrast)

• Diagnostic injection of Thorotrast causes primary liver cancer, leukemia (excluding chronic lymphocytic leukemia), cancer of the extrahepatic bile ducts, and of the gallbladder

• Also, positive associations have been observed between injection of Thorotrast and cancer of the pancreas and of the prostate.

• There is sufficient evidence in humans for the carcinogenicity of plutonium-239

• Plutonium-239 causes cancer of the lung, liver and bone

• There is limited evidence in humans for the carcinogenicity of mixtures of uranium isotopes

• There is sufficient evidence in experimental animals for the carcinogenicity of 210Po, 222Rn, 224Ra, 226Ra, 228Th, 230Th, 232Th, 233U, 234, 235, 238U (natural, enriched and depleted uranium), 237Np, 238Pu, 239Pu, 241Am, 244Cm, 249Cf, 252Cf

Final Evaluation: α-Emitting Radionuclides

• Radon-222 with its decay products are carcinogenic to humans (Group 1)

• Radium-224, radium-226, radium-228 are carcinogenic to humans (Group 1)

• Thorium-232 (as Thorotrast) is carcinogenic to humans (Group 1)

• Plutonium-239 is carcinogenic to humans (Group 1)

• The Working Group noted that human exposure to plutonium-239 may also include exposure to other plutonium isotopes

• Underground hematite mining with exposure to radon is carcinogenic to humans (Group 1)

• Internalized radionuclides that emit α-particles are carcinogenic to humans (Group 1)

Final Evaluation Considerations: α-Emitting Radionuclides

• α-Particles emitted by radionuclides, irrespective of their source, produce the same pattern of secondary ionizations, and the same pattern of localized damage to biological molecules, including DNA. These effects, observed in vitro, include DNA double-strand breaks, chromosomal aberrations, gene mutations, and cell transformation.

• All radionuclides that emit α-particles and that have been adequately studied, including radon-222 and its decay products, have been shown to cause cancer in humans and in experimental animals.

• α-Particles emitted by radionuclides, irrespective of their source, have been shown to cause chromosomal aberrations in circulating lymphocytes and gene mutations in humans in vivo.

• The evidence from studies in humans and experimental animals suggests that similar doses to the same tissues - for example lung cells or bone surfaces - from α-particles emitted during the decay of different radionuclides produce the same types of non-neoplastic effects and cancers.

Internalized β-particle Emitting

Radionuclides

Cancer in Humans• Pure β-particle emitters

• Tritium

• Phosphorus-32

• Mixed exposures

• Caesium-137

• Fission products

• Mixed β-particle emitters – radioiodines

Cancer in Humans• Few epidemiological studies have assessed the carcinogenic effects of 3H intakes in human

populations

• Typically low doses encountered in occupational and environmental

• Studies on UKAEA workers noted a significantly elevated relative risk of prostate cancer among workers with documented intake of 3H that tended to increase in magnitude with duration of 3H monitoring

• 3H doses were not quantified and there is potential for confounding by other occupational exposures

• Epidemiological literature provides consistent evidence of an elevated risk of leukaemia among patients treated with 32P

• Study on polycythemia-vera patients showed a significant association between 32P treatment and the occurrence of acute leukemia

• A dose–response association between 32P and leukemia

• No new study was available to the working group that allowed the evaluation of the possible carcinogenic effect of 137Cs on its own

Cancer in Humans• Based on increased risk of solid cancers and of leukemia among residents of the Techa

River it was considered by IARC that the mixture of external exposure and internal exposures predominantly to 90Sr causes cancer in humans

• The evidence relating risk of thyroid cancer and exposure to radioiodines in childhood and adolescents from the Chernobyl accident has increased substantially

• Increased risks are also suggested for exposure to radioiodines from fallout from the Nevada and Marshall Islands atmospheric weapons tests

• The effect of exposures to radioiodines from fallout on the risk of tumors other than the thyroid has not been studied adequately

• More recent studies of cohorts of patients treated with 131I indicate an increased risk of cancer

• Apparent activity-related increases were observed for tumors of the salivary gland and digestive tract, for leukemia and for bone and soft tissue sarcoma, but not for breast cancer

Evaluation: β-Emitting Radionuclides

• There is sufficient evidence in humans for the carcinogenicity of exposure during childhood and adolescence to short-lived radioisotopes of iodine, including iodine-131

• Exposure during childhood and adolescence to short-lived radioisotopes of iodine, including iodine-131, causes cancer of the thyroid

(Positive associations have been observed between exposure to iodine-131 and cancer of the digestive tract and salivary gland, leukemia, and bone and soft tissue sarcoma)

• There is sufficient evidence in humans for the carcinogenicity of therapeutic administration of phosphorus-32, as phosphate

• Therapeutic administration of phosphorus-32, as phosphate, causes acute leukemia in patients with polycythemia-vera

• There is sufficient evidence in humans for the carcinogenicity of external exposure and internal exposure to fission products, including strontium-90

• External exposure and internal exposure to fission products, including strontium- 90, causes solid cancers and leukemia

Evaluation: β-Emitting Radionuclides

• There is limited evidence in humans for the carcinogenicity of strontium-90. A positive association has been observed between exposure to strontium-90 and leukemia.

• There is inadequate evidence in humans for the carcinogenicity of hydrogen-3.

• There is inadequate evidence in humans for the carcinogenicity of caesium-137 alone or in combination with external radiation.

• There is sufficient evidence in experimental animals for the carcinogenicity of the following β-emitting radionuclides: 3H, 32P, 90Sr, 90Y, 91Y, 131I, 137Cs, 144Ce, 147Pm, 228Ra.

• There is limited evidence in experimental animals for the carcinogenicity of calcium-45 and Lutetium-177.

Final Evaluation: β-Emitting Radionuclides

• Short-lived radioisotopes of iodine, including Iodine-131 (131I), are carcinogenic to humans (Group 1)

• Phorphorus-32 (32P), as phosphate, is carcinogenic to humans (Group 1)

• Mixtures of fission products are carcinogenic to humans (Group 1)

• Internalized radionuclides that emit β particles are carcinogenic to humans (Group 1)

Final Evaluation Considerations: β-Emitting Radionuclides

• β-Particles emitted by radionuclides, irrespective of their source, produce similar patterns of secondary ionizations and the same type of localized damage to biological molecules, including to DNA. These effects include DNA double strand breaks, chromosomal aberrations, gene mutations and cell transformation.

• All radionuclides that emit β-particles and that have been adequately studied, have been shown to cause cancer in humans and in experimental animals. This includes hydrogen-3, which produces β-particles of very low energy, but for which there is nonetheless sufficient evidence of carcinogenicity in experimental animals.

• β-Particles emitted by radionuclides, irrespective of their source, have been shown to cause chromosomal aberrations in circulating lymphocytes and gene mutations in humans in vivo.

• The evidence from studies in humans and experimental animals suggests that similar doses to the same tissues -for example lung cells or bone surfaces - from β-particles emitted during the decay of different radionuclides produce the same types of non-neoplastic effects and cancers

Radiation Exposures with Sufficient Evidence in Humans

All types of ionizing radiation are carcinogenic to humans (Group 1)

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