ETX 135: Health Risk Assessment of Toxicants - Dose-Response (Cancer)

Health Risk Assessment of Toxicants

Overview of Cancer and Carcinogens

  • Definition of Cancer:

    • Uncontrolled growth of abnormal cells.
    • Considered a complex, multistage process with many different diseases exhibiting common traits.
    • Factors contributing to cancer can be classified as external (environmental) or internal (genetic).

  • Carcinogens:

    • Defined as agents that cause neoplasms (tumors):
    • Dysplasia: Abnormal cell growth.
    • Invasiveness: Tumors invade neighboring tissues.
    • Metastasis: Tumor cells migrate to distant sites.
Carcinogen Examples
  • Known human carcinogens include:
    • Nickel (Nasal sinus and lung cancers)
    • Vinyl chloride (Angiosarcoma of the liver)
    • Asbestos (Lung and mesothelioma)
    • Benzene (Leukemia)
Cancer Mechanisms
  • Carcinogenesis: Includes:
    • Somatic mutations: Changes in proto-oncogenes and tumor suppressor genes.
    • Mechanisms: Genotoxic and non-genotoxic pathways.
    • Multiple factors: Both genetic factors such as mutations, and environmental factors such as exposure to chemicals or radiation can contribute to tumor development.
IARC Classification of Carcinogens
  • Group 1: Carcinogenic to humans (e.g., tobacco smoke, solar radiation).
  • Group 2A: Probably carcinogenic (limited evidence in humans, sufficient in animals).
  • Group 2B: Possibly carcinogenic.
  • Group 3: Not classifiable due to lack of evidence.
Cancer Potency Factor Calculation
  • Benchmark Dose (BMD): Determined using dosimetry to calculate the cancer potency factor, often defined in terms of excess lifetime risk per unit dose (e.g., 1.5imes10−21.5 imes 10^{-2} per mg/kg-day).
  • Methodology for Assessment:
    • Use mathematical models (linearized multistage model) to determine cancer risk from exposure.
    • Potency is generally assessed in terms of the slope of the dose-response curve at low doses.
Differences Between Cancer and Non-Cancer Risk Assessments
  • Cancer risk:
    • Quantal and stochastic nature: either present or absent, manifesting years after exposure.
    • Linear relationship with low doses without threshold, leading to risks even at very low exposures.
Data Sources for Cancer Dose-Response Assessments
  • Human Studies: Epidemiological studies (cohort and case-control studies) rely heavily on a sufficient population size and accuracy of exposure assessment.
    • Advantages include direct relevance but can suffer from limitations in sensitivity and needing extensive controls for confounding factors.
  • Animal Bioassays: Experimental studies provide more controlled data, typically identifying carcinogenic risks before human exposure impacts are seen.
Modeling and Extrapolation Techniques
  • Benchmark Dose Methodology:
    • BMDL is the lower confidence limit for effects observed at a specified response (like 10%).
    • Modeling must account for dose-response relationships in both human and animal cohorts.
Special Considerations for Sensitive Populations
  • Infants and children may exhibit increased sensitivity to carcinogens due to physiological differences and developmental stages.
  • Adjustment factors for risk assessments often include:
    • Young age intervals (e.g., <2 years, 2-16 years).
    • These approaches help characterize the potential for increased lifetime cancer risk.
Calibration of Potency Across Species
  • Interspecies extrapolation employs body weight scaling (typically BW3/4BW^{3/4}) to assess human equivalent potency from animal data.
  • Effective human cancer potency, for instance, derives from animal potency adjusted for species differences.