Evaluation of Toxicity

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					Evaluation of Toxicity
Module 5
    Risk Assessment Process


Data Collection                      Risk
And Evaluation                  Characterization

Toxicity Assessment

   Identifies what adverse effect a
    chemical is associated with and the
    dose level at which it occurs. Toxic
    effects depend on:
    – Dose
    – Route of exposure (oral, inhalation,
    – Duration of exposure (acute, subchronic,
Non-Cancer Effects

   Toxicity assessments focus on cancer
    and non-cancer health effects
   Non-cancer health effects are known
    or presumed to have a non-linear or
    threshold mode of action
Target Organ Toxicity

 Central Nervous System – lead
 Immune System - isocyanates
 Liver - ethanol, acetaminophen
 Respiratory Tract - tobacco smoke,
                    asbestos, ozone
 Eye - UV light (sunlight)
 Kidney - metals
 Skin - UV light, gold, nickel
 Reproductive System –
Non-Cancer Effects

   Non-cancer risk assessments are not based on the
    threshold, but on the oral Reference Dose (RfD) or
    inhalation Reference Concentration (RfC)
   The RfD is an estimate of a daily exposure (RfD is a
    continuous inhalation exposure) to the human
    population that is likely to be without risk of
    deleterious effects during a lifetime.
   The RfD or RfC can be derived from a no-observed-
    adverse effect level, lowest-observed adverse-effect
    level, or benchmark dose
   Uncertainty factors are applied to reflect limitations
    of the data used
Reference Dose (or
Concentration) Equation
   RfD (or RfC) = NOAEL or LOAEL/ UF
    – RfD (RfC) = Reference Dose (or
    – NOAEL= no observed adverse effect level
    – LOAEL = lowest observed adverse effect
    – UF = uncertainty factors
Uncertainty Factors Applied to a RfD or RfC

10                     Variation in human susceptibility

10                     Uncertainty in extrapolating
                       animal data to humans

10                     Uncertainty extrapolating from
                       less than lifetime exposure

10                     Uncertainty extrapolating from a
                       low to a no observed adverse
                       effect level
10                     Uncertainty extrapolating from an
                       incomplete database
                    Example of a Reference Dose in
                  IRIS Quickview - Inorganic Arsenic
Chronic Health Hazard Assessments for Noncarcinogenic Effects
Reference Dose for Chronic Oral Exposure (RfD)

                       Point of Departure*             UF          MF           RfD
Critical Effect
Hyperpigmentation      NOAEL : 0.0008                    3          1           3 x10 mg/kg-day
   keratosis and         mg/kg-day

   * The Point of Departure listed serves as a basis from which the Oral RfD was derived. See
   Discussion of Conversion Factors and Assumptions for more details.
   •Principal and Supporting Studies (Oral RfD)
        •Human chronic oral exposure, Tseng, 1977; Tseng et al., 1968
   •Confidence in the Oral RfD
        •Study -- Medium
        •Database -- Medium
        •RfD -- Medium
A note on margin of
   Some regulatory agencies use a
    margin of exposure (MOE) approach
   This approach uses the lowest
    observed effect level, without the use
    of uncertainty factors, to compare
    population specific intakes to.
    – MOE = Intake/ Lowest observed effect
Cancer Effects

   Cancer effects are described both
    qualitatively and quantitatively.
   A cancer weight of evidence descriptor
    is used to describe a substance’s
    potential to cause cancer
   This judgment is independent of a
    substance’s potency
  USEPA Guidelines for Carcinogen
     Risk Assessment (2005)
Carcinogenic to Humans

Likely to be Carcinogenic to Humans

Suggestive Evidence of Carcinogenic Potential

Inadequate Information to Assess Carcinogenic
Not Likely to be Carcinogenic to Humans
Cancer Effects

   Cancer effects are described
    quantitatively by the number of
    cancers observed in exposed animals
    or humans and how they increase as
    the dose increases
   The USEPA assumes that the dose-
    response curve has no threshold
Cancer Effects
   Cancer potency is described by the slope of
    the dose-response curve. This is called the
    Slope Factor
   Typically we don’t have data below the
    administered dose levels, so we use
    mathematical models to extrapolate from
    observed high dose data to the slope at low
   USEPA calculates the upper 95th confidence
    limit of the slope as the Slope Factor to
    ensure a margin of safety
    Example of Cancer Information
    on IRIS Quickview for Inorganic
   Carcinogenicity Assessment for Lifetime Exposure
   Weight-of-Evidence Characterization
      – A (Human carcinogen)
   Weight-of-Evidence Narrative:
      – Based on sufficient evidence from human data. An increased lung cancer mortality was observed
         in multiple human populations exposed primarily through inhalation. Also, increased mortality
         from multiple internal organ cancers (liver, kidney, lung, and bladder) and an increased incidence
         of skin cancer were observed in populations consuming drinking water high in inorganic arsenic.
      – This may be a synopsis of the full weight-of-evidence narrative. See IRIS Summary.
   Quantitative Estimate of Carcinogenic Risk from Oral Exposure
   Oral Slope Factor(s): 1.5 per mg/kg-day Extrapolation Method: Time- and dose-related
    formulation of the multistage
   Dose-Response Data (Carcinogenicity, Oral Exposure)
      – Tumor Type: Skin cancer
      – Test Species: Human
      – Route: Oral, Drinking water
      – Reference: Tseng, 1977; Tseng et al., 1968; U.S. EPA, 1988
   Quantitative Estimate of Carcinogenic Risk from Inhalation Exposure
   Inhalation Unit Risk(s) Method: 4.3 x10-3 per ug/m3 Extrapolation: Absolute-risk linear
   Dose-Response Data (Carcinogenicity, Inhalation Exposure)
      – Tumor Type: Lung cancer
      – Test Species: Human, male
      – Route: Inhalation, Occupational exposure
      – Reference: Brown and Chu, 1983a,b,c; Lee-Feldstein, 1983; Higgins, 1982; Enterline and Marsh,
Where do you get toxicity
Sources of Toxicity
   USEPA’s Integrated Risk Information
    System (IRIS) Database
   Agency for Toxic Substances and
    Disease Registry Toxicological Profiles
A Word About Dermal
   Dermal contact with contaminants may result in
    direct toxicity at the site of contact of systemic
    toxicity via absorption
   Oral cancer (slope factors) and non-cancer (RfD)
    toxicity values are used to assess dermal exposure
   Oral toxicity values are based on an administered
    dose. Dermal exposure is an absorbed dose.
   The oral toxicity values must be adjusted by the
    fraction or % of contaminant absorbed in the
    gastrointestinal tract to derive a dermal or
    “absorbed” slope factor.
    Derivation of Cancer Slope
    Factor Based on Absorbed

   SFABS = Absorbed Slope Factor
   SFo = Oral Slope Factor (mg/kg-day)-1
   ABSGI = Fraction of contaminant
    absorbed in gastrointestinal tract
     Derivation of Reference
     Dose Based on Absorbed

   RfDabs = Absorbed Reference Dose
   RfDo = Oral Reference Dose (mg/kg-day)
   ABSGI = Fraction of contaminant absorbed
    in gastrointestinal tract
Classroom Exercise

   Review the IRIS Chemical File for
   Provide the critical health effect, the no- or
    lowest observed effect level, the uncertainty
    factors and the Reference Dose and
    Reference Concentration for non-cancer oral
    and inhalation effects.
   Discussion of inhalation effect level for
    continuous exposure and conversion to a
    human equivalent concentration.

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