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Evaluation of Toxicity Module 5 Risk Assessment Process Toxicity Assessment Data Collection Risk And Evaluation Characterization Exposure Assessment 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, dermal) – Duration of exposure (acute, subchronic, chronic) 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 – dibromochloropropane 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 Concentration) – NOAEL= no observed adverse effect level – LOAEL = lowest observed adverse effect level – 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 -4 Hyperpigmentation NOAEL : 0.0008 3 1 3 x10 mg/kg-day keratosis and mg/kg-day possible vascular complications * 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 exposures 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 level 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 Potential 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 doses 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 Arsenic 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, 1982 Where do you get toxicity information? Sources of Toxicity Information USEPA’s Integrated Risk Information System (IRIS) Database – http://cfpub.epa.gov/ncea/iris/index.cfm Agency for Toxic Substances and Disease Registry Toxicological Profiles – http://www.atsdr.cdc.gov/toxpro2.html A Word About Dermal Toxicity 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 Dose SFABS = SFo/ ABSGI 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 Dose RfDABS = RfDO X ABSGI 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 Manganese 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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