OCCUPATIONAL CANCERS

OCCUPATIONAL CANCERS

Jay Harper, MD, MPH

412-647-5323

harperjd@upmc.edu

Overview

• 2 to 8 % of all cancers are thought to be due to occupational exposures (Doll & Peto)

• Prevention is key

• Environmental as well as occupational cancers

• Multifactorial

History

• 1775: Sir Percival Pott: scrotal cancer in chimney sweeps

• 1895: Bladder cancer: aromatic amines

• 1973: Lung cancer: bis-chloromethylether

• 1974: Liver angiosarcoma: vinyl chloride

Stages of Tumor Development

• Initiation– Active mutation or damage to DNA– Single exposure may be sufficient

(carcinogenic by themselves)– Action is irreversible– No apparent threshold– No morphologic changes in initiated cell– Dependency on metabolism and the cell cycle

Stages of Tumor Development

• Promotion– May speed cell production or suppress

apoptosis– Causes morphologic changes – Modulation by environment and lifestyle– Probable threshold– Reversible

Stages of Tumor Development

• Progression– Additional changes necessary for the

development of a malignant tumor• Likely triggered by genetic events

– Development of invasiveness, metastasis, irreversible changes in genome

– If no progression, then remains at benign stage such as papilloma, nodules or adenoma

EPIDEMIOLOGIC STUDIESCriteria for Causality

• STRENGTH – magnitude of relative risk• CONSISTENCY – reported in multiple

studies with different circumstances• BIOLOGICAL GRADIENT – dose-

response validity• BIOLOGICAL PLAUSIBILITY – “makes

sense’• TEMPORALITY – cause precedes effect

EPIDEMIOLOGIC STUDIES

• Advantages– Allows direct assessment in humans– May detect cancer cluster– Allows observation of cumulative effects of

environmental and lifestyle factors affecting various stages

– Allows estimates of relative risk

EPIDEMIOLOGIC STUDIES

• Disadvantages– Long latency periods– Limited to those materials used for many years– Retirement of workers– Difficulty with small risk: extrapolation

beyond available data, poor-exposure record keeping, poor exposure recall, worker job transfers

– Confounding risk factors cannot be controlled

Animal Studies

• IARC requirements• Good qualitative predictor• Not-so-good quantitative predictor• Limitations

– High dose exposure is needed in order to detect significance

– Different metabolism– Different routes of administration

Short - Term Tests

• Provide evidence of mutagenicity

• Ames test, sister-chromatin exchange, DNA repair

• Quicker results, less expensive

• Correlation of results with animals/humans imperfect

Molecular Biology

• Allows assessment of exposure and possible early health effects

• Measure enzyme activity of the cytochrome p450 monooxygenase class

• Measurement of DNA or protein adducts

• Measurement of protein products in the urine

Regulatory Issues

• If there is sufficient evidence of carcinogenicity, then corrective action is taken, even if uncertainty exists

• Limited evidence should be stimulus for more research

• Risk assessment is crucial to best public policy

Agencies

• IARC: International Agency for Research on Cancer

• ACGIH: American Conference of Governmental Industrial Hygienists

• NTP: US Public Health Service National Toxicology Program

• NIOSH: National Institute for Occupational Safety and Health

IARC

• Group 1 – carcinogenic to humans

• Group 2 – 2A – probably carcinogenic to humans– 2B – possibly carcinogenic to humans

• Group 3 – not classifiable

• Group 4 – probably not carcinogenic to humans

Known Human Occupational Lung Cancers

• Arsenic• Asbestos• Beryllium• Cadmium• Chloromethyl ethers• Chromium

• Coal-related products• Mustard gas• Nickel• Radon• Vinyl chlorine

Lung Cancer - Asbestos

• Chrysotile is the most common form of asbestos (Other forms are amosite, crocidolite, tremolite)

• Asbestos affects parenchyma and pleura of lungs• Can cause cancer of larynx, GI tract (stomach) as

well as lung• Long latency• Synergism with smoking

Asbestos - Mesothelioma

• Uncommon• No evidence for direct relationship• Dose – response relationship exists,

although no threshold theorized• No interaction with smoking• All fiber types may cause mesothelioma

– Crocidolite (long, thin fiber) is the most potent type

Lung Cancer - Chloromethyl ether

• Chloromethyl methyl ether (CMME) and Bis (chloromethyl) ether (BCME)

• BCME more potent then CMME

• Oat cell type

• Intermediate product used in ion-exchange resins, bactericides, pesticides and solvents

Lung Cancer - Chromium

• Hexavalent (+6) form is carcinogenic; other forms are not

• Also causes perforated nasal septum

• Used as hardening agent in metallic compounds

Lung Cancer - Arsenic

• May cause skin cancer, as well as lung cancer• Synergistic with smoking

– Between additive and multiplicative

• Most often seen in upper lobes• Copper smelting and pesticide production• Found in natural and man-made sources

– Seafood source is non-toxic

– Toxic in Fowler’s solution (used for eczema/psoriasis) and pesticides (vineyard workers)

Lung Cancer - Nickel

• Associated with lung, nasal and laryngeal cancers

• Nickel mining and refining

• Soluble forms are more potent

• Squamous cell most common type

• Good housekeeping is especially important for reducing occupational exposure

Lung Cancer - Coal-related products

• PAH – Polyaromatic Hydrocarbon• Known carcinogens are benz(a)anthracene and

7,12 dimethylbenzanthracene• Lung cancer is seen in coke-oven workers; scrotal

cancer in chimney sweeps• PAH’s are formed through incomplete combustion

of coal, tar, coke and oil• PAH’s found in coal gasification facilities, gas and

coke works, iron and steel foundries, petroleum distillates and diesel exhaust.

Lung Cancer - Mustard Gas

• Bis (beta-chloroethyl) sulfide

• Poisonous gas used in WWI

• Causes squamous cell lung CA

• Excess lung cancers seen in Japanese and German workers manufacturing mustard gas

Lung Cancer - Radon

• “Wasting disease of the mountains” seen in miners by Agricola and Paracelsus

• Radon daughter products

• Cigarette smoking acts synergistically with radon

• Lifetime dose in certain dwellings is concern

Prevention of Occupational Lung Cancer

• Primary prevention is important– Smoking cessation

• Secondary prevention (medical monitoring)– OSHA mandates monitoring for asbestos,

acrylonitrile, arsenic, silica, and vinyl chloride– NIOSH recommends monitoring for beryllium,

carbon black, chromium VI, coal tar products, inorganic nickel and coal gasification

– Chemopreventive agents

Upper Respiratory Cancers

• Sino-nasal– Nickel, wood dust, chromium , cutting oils,

mustard gas

• Laryngeal– Asbestos, nickel, mustard gas, cutting oils

Hematologic Cancers

• Risk Factors– Ionizing radiation– Benzene– Agricultural work– Cytotoxic drugs

Hematologic Cancer - Ionizing Radiation

• Studies from atomic blasts from WWII

• Associated with all leukemia types except CLL

• ALARA (as low as reasonably achievable)

Hematologic Cancer - Benzene

• Associated with pancytopenia and AML

• Industrial rubber workers, refinery workers, chemical workers (soaps, dyes, cosmetics, perfumes), explosives industry

• Safe exposure level unknown

Hematologic Cancer - Agricultural Exposure

• Farmers

• Multiple etiologies, including pesticides and herbicides

• Leukemia, Multiple Myeloma, Hodgkin’s Disease and Non-Hodgkin’s Lymphoma

Hematologic Cancer - Medical Exposures

• Anti-neoplastic drugs

• Ethylene oxide

• Radiation

Bladder Cancer

• Especially dye/pigments and tire/rubber mfg.• Up to 20% of bladder CA related to occupation• Kidney concentrates toxin; prolonged exposure in

bladder• Benzidene• 2-Naphylamine• 4-Nitrobiphenyl• 4,4-methylene-bis-(2-chloroaniline) or MOCA• 4,4-methylene dianiline or MDA

Bladder Cancer Screening

• Hematuria – high risk populations only

• Urine cytology

• Newer areas of detection: quantitative fluorescence image analysis (QFIA) and DNA flow cytometry.

• Sensitivity/specificity issues

Bladder Cancer Screening

• NIOSH recommendations– Screening for bladder cancer should be viewed

as a research endeavor whose benefits are not yet delineated

– Screening techniques are evolving; it would be wise to bank serum and urine samples

– Natural history of bladder CA is unclear, thus the value of detecting superficial versus invasive lesions is unclear

GI Tract

• Gastric– Asbestos, wood dust, rubber industry

• Colon– Sedentary work is risk factor– Asbestos and rubber industry suspected– Screening (Digital Rectal Exam vs. stool guiac

vs. sigmoidoscopy)

GI Tract - Liver

• Hepatitis B&C, alcohol, aflatoxins

• Asbestos suspected

• Solvents associated with hepatic fibrosis

• Hepatic Angiosarcoma– Vinyl chloride– Thorotrast– Arsenic

Skin Cancer

• Ionizing radiation

• Arsenic

• Polycyclic aromatic hydrocarbons

• UV radiation