1. Michael H. Dong MPH, DrPA, PhD readings Characterization of Health Risk (9th of 10 Lectures on Toxicologic Epidemiology)

2. Taken in the early ’90s, when desktop computers were still a luxury.

3. 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.

4. 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.

5. 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 Handbook RC is and isn’t part of RA.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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. benchmark dose

11. 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.

12. 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.

13. 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).

14. Risk Analysis (IV) HX (hazard index) is another direct measure used for multiple routes and sources of exposure; HX = HQ 1 + HQ 2 +... + HQ n. For cumulative exposures to multiple chemicals having a common mode of toxicity, HX =  [HQ mn ) x (RP mn )], where RP mn is potency for mth chemical and nth route or source, relative to that of the index chemical.

15. 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.

16. 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.

17. 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.

18. 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.

19. 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).

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.

26. 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.

27. Overview of Final Lecture Toxicologic 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.