OCCUPATIONAL CANCERS

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OCCUPATIONAL CANCERS

• Jay Harper, MD, MPH
• 412-647-5323
• harperjd_at_upmc.edu

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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

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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

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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

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Stages of Tumor Development

• Promotion
• May speed cell production or suppress apoptosis
• Causes morphologic changes
• Modulation by environment and lifestyle
• Probable threshold
• Reversible

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Known Human Occupational Lung Cancers

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

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

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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

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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

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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

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Lung Cancer - Chromium

• Hexavalent (6) form is carcinogenic other forms
  are not
• Also causes perforated nasal septum
• Used as hardening agent in metallic compounds

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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 Fowlers solution (used for
  eczema/psoriasis) and pesticides (vineyard
  workers)

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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

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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
• PAHs are formed through incomplete combustion of
  coal, tar, coke and oil
• PAHs found in coal gasification facilities, gas
  and coke works, iron and steel foundries,
  petroleum distillates and diesel exhaust.

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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

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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

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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

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Upper Respiratory Cancers

• Sino-nasal
• Nickel, wood dust, chromium , cutting oils,
  mustard gas
• Laryngeal
• Asbestos, nickel, mustard gas, cutting oils

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Hematologic Cancers

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

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Hematologic Cancer - Ionizing Radiation

• Studies from atomic blasts from WWII
• Associated with all leukemia types except CLL
• ALARA (as low as reasonably achievable)

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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

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Hematologic Cancer - Agricultural Exposure

• Farmers
• Multiple etiologies, including pesticides and
  herbicides
• Leukemia, Multiple Myeloma, Hodgkins Disease and
  Non-Hodgkins Lymphoma

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Hematologic Cancer - Medical Exposures

• Anti-neoplastic drugs
• Ethylene oxide
• Radiation

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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

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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

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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

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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)

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GI Tract - Liver

• Hepatitis BC, alcohol, aflatoxins
• Asbestos suspected
• Solvents associated with hepatic fibrosis
• Hepatic Angiosarcoma
• Vinyl chloride
• Thorotrast
• Arsenic

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Skin Cancer

• Ionizing radiation
• Arsenic
• Polycyclic aromatic hydrocarbons
• UV radiation