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Characterization of Health Risk (9th of 10 Lectures on Toxicologic Epidemiology). Michael H. Dong MPH, DrPA, PhD. readings. Taken in the early ’90s, when desktop computers were still a luxury. Learning Objectives Study the steps involved in health risk characterization (RC).

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of Health Risk

(9th of 10 Lectures onToxicologic Epidemiology)

Michael H. Dong



Learning Objectives
  • Study the steps involved in health risk characterization (RC).
  • Learn about the measures and terms used in risk analysis.
  • Learn about the numerous ways to compare an exposure to a safe level.
  • Study the major issues and the uncertainties involved in RC.
Performance Objectives
  • Able to account for the major steps undertaken to perform health risk characterization (RC).
  • To list and define the measures used to denote a risk as insignificant.
  • To describe the numerous ways in which a health risk can be assessed.
  • To highlight the issues pertaining to the uncertainties in RC.

Risk Characterization vs. Risk Assessment

  • RC is the process wherein the risk is characterized, and thus is the final step of RA.
  • Technical definition is given in USEPA’s RC Handbook.
  • RC is and isn’t part of RA.

Framework and Role of Risk Characterization

  • RC is basically a quantitative process comparing an exposure level to a safe level.
  • RC is performed under the premise that health risk is proportional to exposure level.

Role/Issues of Hazard Identification (HI)

  • HI is a complex process in which adverse effects are determined.
  • It should be based on well-designed, well-conducted toxicity studies.
  • In this process, risk assessors need to determine which adverse effects as toxic endpoints of concern.

Considerations and Procedures of HI

  • Weight-of-evidence and credibility of toxicity studies all play a critical role in Hazard Identification.
  • Once the endpoint(s) is identified, the next step is to determine the highest no observed effect level.

Functions of Dose-Response Assessment (I)

  • To ascertain the lowest observed effect level, or the highest dose as the no observed effect level.
  • To aid in interpreting toxicity data.
  • A steeper slope suggests that the responses are more dose-sensitive.

Functions of Dose-Response Assessment (II)

  • It plays a prominent role in assessing no threshold adverse effect.
  • Its data can be used for high-to-low dose extrapolation.
  • Its data can also be used to derive a benchmark dose for getting a more accurate lowest observed effect level.

Risk Analysis (I)

  • ADI (acceptable daily intake) is a predetermined lifetime dose that can be ingested daily without causing appreciable adverse effects.
  • RfD (reference dose), RfC (reference concentration), and ADI each = (NOEL)/(SF), where SF = a safety factor and NOEL = no observed effect level; their SF may vary.

Risk Analysis (II)

  • PEL (permissible exposure limit), TLV (threshold limit value), and STEL (short-term exposure limit) are maximum allow-able air levels of industrial chemicals.
  • MCL is maximum contaminant level in (e.g., drinking) water.
  • BMD is benchmark dose yielding a better measure of lowest or no effect level.
  • ECR (excess cancer risk) = (dose) x (CPF), where CPF = cancer potency factor.

Risk Analysis (III)

  • Indirect risk measures include: ADI, RfD, NOEL, CPF, PEL, etc.
  • ECR is a direct risk measure for carcinogenic effects.
  • For other effects, MOE (margin of exposure) and HQ (hazard quotient) are used as direct risk measures.
  • MOE = NOEL/dose = SF/HQ (where SF = safety factor).

Risk Analysis (IV)

  • HX (hazard index) is another direct measure used for multiple routes and sources of exposure; HX = HQ1 + HQ2 + . . . + HQn.
  • For cumulative exposures to multiple chemicals having a common mode of toxicity, HX =  [HQmn) x (RPmn)], where RPmn is potency for mth chemical and nth route or source, relative to that of the index chemical.

Uncertainties in Risk Characterization (RC)

  • Safety factors are incorporated into the risk calculation; uncertainties are inherent in toxicity assessment and in human exposure assessment.
  • RC could take months or years to complete, due to difficult resolution of these uncertainties.
  • Uncertainty differs from variability.

Uncertainties in TA (I)

  • Interspecies is one of the most critical issues in Toxicity Assessment.
  • The strength- and weight-of-evidence in TA are ever lacking and, in most cases, difficult to assess or resolve.
  • Also lacking is solid evidence that can support the adequacy of the uncertainty factor of 10 used for interspecies difference.

Uncertainties in TA (II)

  • Systemic endpoints are usually from oral doses; yet dermal acquisition typically takes place incrementally, making Toxicity Assessment difficult to perform.
  • Oral absorption generally is also faster, whereas the dermal route requires a chemical to pass through layers of cells.
  • The metabolic pathways involved may be quite different between a dermal and an oral dose.

Uncertainties in TA (III)

  • Even though the uncertainty factor (UF) of 10 for intraspecies is adequate for healthier worker groups, it may or may not be enough for the general population.
  • This UF needs to be considered in determining the reference dose, thus part of the task in Toxicity Assessment.
  • The UF of 10 for estimating NOEL (no observed effect level) from LOEL (lowest observed effect level) may be inadequate.

Uncertainties in HEA (I)

  • Uncertainties in Human Exposure Assessment are likewise enormous and even more overwhelming.
  • The issues on use of surrogate data are most common, critical, and problematic.
  • It is questionable, for example, that reentry exposure would increase linearly with dislodgeable foliar residues (DFR), even though it is often calculated as the product of (transfer rate) x (DFR).

Uncertainties in HEA (II)

  • In Human Exposure Assessment, issues on surrogacy and other uncertainties may be more transparent in assessing residential and handler exposures.
  • Handler exposure may not be propor-tional to amount of material handled.
  • Values for timed inhalation volume for swimmers vary, depending more on swimming style and physical build.
  • Dermal permeability coefficients may also depend on how skin is treated.

Uncertainties in HEA (III)

  • Another concern in Human Exposure Assessment is younger children may behave differently indoors or outdoors.
  • And the frequency of their hand-to-mouth movements remains uncertain.
  • Unrealistic to assume a worst-case using the most conservative values for all exposure-related parameters.
  • Values of many variables covered in USEPA’s Exposure Factor Handbook may not be useful for worker groups.

Uncertainties in HEA (IV)

  • In Human Exposure Assessment, it is not easy to give an accurate account of all the exposure events for a given day.
  • It is even harder to determine the exact annual or seasonal exposure frequency.
  • Workers could work for multi-growers, for multi-crops, or for multi-fields.
  • Older children usually act differently and have different eating habits than younger children.

Uncertainties in HEA (V)

  • Exposure parameter values are often based on data from unrepresentative, small spot or grab samples.
  • Human biological monitoring, which is the more direct measurement method in Human Exposure Assessment, also has limitations: specificity and sensitivity of the analytical method used; ethical issues; knowledge of chemical’s pharmacokinetics, etc.

Other Uncertainty Issues (I)

  • Risk characterization should include a section on uncertainties with toxicity assessment, and another on those with human exposure assessment.
  • Some uncertainties, such as the issues on dermal absorption, are trivial.
  • Risk or exposure appraisal thus should focus on those uncertainties more unique or more specific to the exposure scenario under study.

Other Uncertainty Issues (II)

  • Mean values should be used instead of upper-bounds even for acute exposure.
  • Larger safety factor (SF) could be used to correct the deficiency from utilizing mean value(s) that may underestimate the risk calculated for acute exposure (which could occur in a single worst day).
  • This SF approach would eliminate the use of unstable or unrealistic statistics.

Other Uncertainty Issues (III)

  • FQPA of 1996 was enacted to respond to society’s special health concern with U.S. children, mandating the consideration of aggregate and cumulative exposure assessments.
  • Through later court and regulatory realizations, the Delaney clause that imposes zero cancer tolerance in the USA has changed to accepting a practical de minimus excess cancer risk of 1 x 10-6.

Overview of Final LectureToxicologic Epidemiology

  • The real intent of this series is to offer a sense of where, what, and how this new health science discipline is growing into.
  • This attempt is indeed the focus of discussion in the next and final lecture.
  • Also to be discussed in Lecture 10 are some career opportunities in this field.