Grantee Research Project Results
Final Report: Alternative Strategies for Quantification of Non-Cancer Health Risks, Utilizing Human Information on Interindividual Variability
EPA Grant Number: R825360Title: Alternative Strategies for Quantification of Non-Cancer Health Risks, Utilizing Human Information on Interindividual Variability
Investigators: Hattis, Dale , Goble, Robert
Institution: Clark University
EPA Project Officer: Aja, Hayley
Project Period: November 18, 1996 through November 17, 1999 (Extended to December 1, 2000)
Project Amount: $331,537
RFA: Exploratory Research - Human Health (1996) RFA Text | Recipients Lists
Research Category: Human Health
Objective:
The basic aim was to develop methods for quantifying non-cancer health effects utilizing human data on the interindividual variability in susceptibility to toxicity and variability in functional reserve capacities for different physiological processes.
Summary/Accomplishments (Outputs/Outcomes):
- We built an extensive database of observations of human interindividual variability in pharmacokinetic and pharmacodynamic parameters relevant to the assessment of the risks of various kinds of toxic effects.
- Utilizing this database, we developed an approach for assessing the human variability associated with various steps in the causal process from external exposure to the manifestation of toxic responses of different types and various degrees of severity.
- From the spread of the pharmacokinetic and pharmacodynamic variability observations in the most statistically robust data sets from the central estimates of variability, we made a quantitative estimate of the uncertainty in interindividual variability that should be associated with model predictions of interindividual variability in susceptibility for chemicals and effects that have not been directly studied in humans. Considering both the variability and the uncertainty in variability, we have developed methods for assessing arithmetic mean "expected value" estimates of risks of individual threshold effects that can be used for regulatory impact assessments and juxtapositions of benefits and costs.
- We analyzed the implications of our estimates of variability (and the uncertainty in those estimates) for the degree of protection likely to be provided by the standard 10-fold uncertainty factor for human variability, acting in isolation. (This 10-fold factor is nearly always used to reflect potential differences in susceptibility among humans both in standard assessments of "Reference Doses" by EPA and in analogous assessments of "Acceptable Daily Intakes" and similar guidelines by food and environmental protection authorities in many countries. Thus, our work provides an opportunity to do at least an initial preliminary quantitative assessment of the operating performance of risk management standards that have been widely applied.)
- In our most recent work, we combined our distributional estimates of human variability with distributional estimates of the adjustments covered by other uncertainty factors (e.g., animal/human, subchronic/chronic, and database incompleteness factors) to assess the population risks, and associated uncertainties inherent in the oral reference doses documented in 20 randomly selected entries in the EPA's IRIS compilation. Part of this and/or other related publications will be a series of sensitivity analyses analyzing how the risk/uncertainty distributions would change if further research were to greatly reduce the uncertainty for each of the uncertainty factors in the analysis. We also will assess the changes in risk that would be expected if there were various amounts of bimodality in the susceptibility variability distributions.
- We also have done appreciable work assessing one indirect method for assessing some noncancer risks?the use of changes in birth weight distributions to predict potential infant mortality risks. Briefly, we used national birth record information to compare the incidence of infant morality associated with cigarette smoking with what would be predicted from: (1) the effect of cigarette smoking on birth weights and gestational ages at birth, and (2) the generic relationships between birth weights and gestational ages to infant mortality observed for all newborns.
In work extending beyond the official conclusion of the project, we are scheduled to present a paper reporting on the analysis described in "5" above and submit it for journal publication. The abstract of this presentation is included as Appendix B of this annual report. We also have arranged to make the data and analysis methods developed in the course of this work freely available via our Web site and continuing collaboration with other researchers.
Journal Articles on this Report : 4 Displayed | Download in RIS Format
| Other project views: | All 10 publications | 5 publications in selected types | All 4 journal articles |
|---|
| Type | Citation | ||
|---|---|---|---|
|
|
Hattis D, Banati JP, Goble R, Burmaster DE. Human interindividual variability in parameters related to health risks. Risk Analysis 1999;19(4):711-726. |
R825360 (Final) |
Exit |
|
|
Hattis D, Banati P, Goble R. Distributions of individual susceptibility among humans for toxic effects: how much protection does the traditional tenfold factor provide for what fraction of which kinds of chemicals and effects? Annals of the New York Academy of Sciences 1999;895:286-316. |
R825360 (Final) |
Exit |
|
|
Hattis D, Anderson EL. What should be the implications of uncertainty, variability, and inherent "biases"/"conservatism" for risk management decision-making? Risk Analysis 1999;19(1):95-107. |
R825360 (Final) |
Exit |
|
|
Hattis D, Swedis S. Uses of biomarkers for genetic susceptibility and exposure in the regulatory context. Jurimetrics 2001;41(2):177-194. |
R825360 (Final) |
not available |
Supplemental Keywords:
interindividual variability, uncertainty factors, risk assessment, risk, health effects, vulnerability, sensitive subpopulations, chemicals, toxics, public policy, decision making, cost benefit, individual thresholds, pharmaceuticals, pharmacokinetics, pharmacodynamics, functional reserve, human clinical studies, contact rates, absorption, systemic elimination, half-life, clearance, volume of distribution., Health, RFA, Scientific Discipline, Toxics, National Recommended Water Quality, Susceptibility/Sensitive Population/Genetic Susceptibility, Ecological Risk Assessment, Risk Assessments, genetic susceptability, Children's Health, Biochemistry, causal chain, toxic environmental contaminants, environmental hazard exposures, health risks, sensitive populations, neurotoxic, lead, inter-individual variation, cadmium, human exposure, pharmokinetic models, toxicology, biomarker, human data, stochastic models, air pollution, kidney function, quantification of non-cancer riskRelevant Websites:
Human Interindividual Variability in Parameters Related to Susceptibility for Toxic Effects Exit
Progress and Final Reports:
Original AbstractThe perspectives, information and conclusions conveyed in research project abstracts, progress reports, final reports, journal abstracts and journal publications convey the viewpoints of the principal investigator and may not represent the views and policies of ORD and EPA. Conclusions drawn by the principal investigators have not been reviewed by the Agency.