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Critical Aspects of EPA's IRIS Assessment of Inorganic Arsenic Interim Report (2013) / Chapter Skim
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7 DoseResponse Analysis
Pages 76-83

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From page 76...
... DOSE–RESPONSE ANALYSIS FOR NONCANCER AND CANCER END POINTS The committee recognizes that quantitative dose–response analyses are one of the major functions of the IRIS program and that the extrapolations involved in this process are among the most controversial aspects of arsenic risk assessment. There has been a substantial expansion of epidemiologic studies of associations between arsenic exposure and a variety of health outcomes, including cardiovascular disease, diabetes, nonneoplastic respiratory changes, skin lesions, pregnancy, child development, skin cancers, bladder cancers, and lung cancers; the studies increasingly characterize risks of the health outcomes at low to moderate arsenic exposures.
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From page 77...
... By providing both the dose–response function and a series of risk-specific doses, the IRIS assessment for inorganic arsenic will go beyond typical IRIS assessments, which develop a single RfD, and will facilitate an array of analyses, including cumulative risk assessment, benefit–risk ratios, and other comparative and economic analyses. For both cancer and noncancer end points, consideration of the methods used in the epidemiologic study analyses will be important in developing the dose–response analysis in the observed range.
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From page 78...
... report carried out a sensitivity analysis of the effect of alternative assumptions concerning dietary exposures on risk estimates. A challenge that the IRIS program will need to address in using these studies is that they have characterized arsenic exposures by using different metrics (such as urinary arsenic or water concentrations)
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From page 79...
... based on the dataset were adjusted for appropriate covariates, but additional data are not available. TABLE A Summary Data on Cardiovascular-Disease Mortality from a Hypothetical Cohort Study Urinary Arsenic, µg/g of creatinine Midpoint Relative Risk <5 3.5a 1.0 5-10 7.5 1.05 10-15 12.5 1.2 >15 18 2.2 a Without additional information about the urinary arsenic concentrations below 5 µg/g of creatinine, a midpoint was set to 5/√2, following guidelines for adjusting for limits of detection.
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From page 80...
... s d the refer rence group) , one could use this comm , mittee's recom mmended app proach of exte ending the do ose– respons curve below the range of observed data points an into the "re se w o d nd eference" pop pulation expos sure levels.
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From page 81...
... The committee's recommendations are made specifically for the IRIS assessment of inorganic arsenic and should not be interpreted as applying to other IRIS assessments, given the robust epidemiologic data available related to exposures approaching background. Animal and in vitro studies have important roles to play in evaluating arsenic health risks by providing controlled experimental findings relevant to causality, mode of action, tissue dosimetry of specific metabolites, and other aspects of arsenic toxicology; they are not the focus of the dose–response analysis in the way that they are for many other chemicals.
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From page 82...
... Although the direct incorporation of mode-of-action data into the analysis of dose–response data from human studies is challenging, biologic-response data could potentially inform the conduct and interpretation of the dose–response analysis on the basis of data from epidemiologic studies. SENSITIVE POPULATIONS AND LIFE STAGES IRIS assessments have long considered sensitive populations and life stages for noncancer end points but less frequently for cancer, although the Supplemental Guidance for Assessing Susceptibility from Early-Life Exposure to Carcinogens provided guidance on chemicals acting through a mutagenic mode of action (EPA 2005a)
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From page 83...
... IRIS USABILITY The success of the IRIS assessment of inorganic arsenic will depend in part on its usefulness to IRIS partners in EPA and to stakeholders, including state, local, and tribal agencies throughout the country and internationally. The committee recommends a number of approaches that are not typical of IRIS assessments, such as providing risk estimates for noncancer outcomes for which a risk-specific dose could be derived.
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Key Terms

  • epidemiologic studies
  • iris assessment
  • iris program
  • urinary arsenic
  • risk estimates

  • arsenic exposure
  • epidemiologic data
  • health risks
  • nonlinear model
  • life stages

  • arsenic concentrations
  • drinking water
  • sensitive populations
  • iris assessments
  • moderate exposures

  • observed data
  • arsenic risk
  • draft iris
  • arsenic exposures
  • arsenic health

  • cancer risk
  • arsenic forms
  • epidemiologic observations
  • cumulative risk
  • effects observed

  • committee judged
  • dietary exposures
  • response analyses
  • mechanistic studies
  • throughout life


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