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Replacing Default Values for Uncertainty Factors with
Chemical Specific Adjustment Factors: Reducing Uncertainty in
Noncancer Risk Assessment
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A tutorial
workshop Society
for Risk Analysis Annual Meeting Half-day
PM course Lake
Buena Vista Palace PRE-REGISTRATION DEADLINE IS NOVEMBER 4, 2005 This half-day workshop will teach the participants methods for application of the new IPCS guidance on the use of chemical-specific adjustment factors (CSAFs), as a refinement to the uncertainty factor approach. A brief review of the use of uncertainty factors and historical perspective on the reliance on quantitative data to develop values for inter- and intraspecies extrapolation will be presented as background. Examples and classroom activities will be used as instructional aids. Synopsis
The World Health Organization, through the International Programme on Chemical Safety (IPCS), has recently established guidance on the use of mechanistic data to replace default uncertainty factors for interspecies extrapolation and intraspecies variability in deriving risk values such as Reference Doses (RfDs) and Tolerable Concentrations (TCs). This guidance informs the choice and application of data that can be used to replace defaults with chemical specific adjustment factors (CSAFs). CSAFs fall on the continuum of the use of data in deriving risk values. At one end of the continuum is the use of the traditional defaults, while at the other end is the use of extensive chemical-specific data in physiologically-based pharmacokinetic (PBPK) modeling, or even biologically-based dose-response (BBDR) modeling. In between these two extremes are the use of categorical defaults, such as the dosimetric approach used in the U.S. EPA’s RfC and cancer risk assessment methods, and CSAFs. The CSAF framework is based on early work by Renwick and applied by IPCS. This approach first subdivides the uncertainty factors for interspecies differences (UFA) and human variability (UFH) into toxicokinetic (TK) and toxicodynamic (TD) components. The data relevant for each subcomponent is then evaluated to determine whether chemical-specific data can be used in place of the default. Any one or all of these four subfactors can be replaced by chemical-specific data. In the absence of chemical-specific data, default values of 2.5 and 4.0 have established for the TD and TK component of UFA, while the default values for the TD and TK components UFH were each established at one-half order of magnitude (3.2). Use of the CSAF framework allows the improved use of available data in deriving risk values, and can assist in targeting new studies to address uncertainties and lead to more accurate risk values. CSAFs have been used by the U.S. EPA in deriving an RfD for boron and by Health Canada in deriving a TC for 2-butoxyethanol. This half-day workshop will provide a brief review of the use of uncertainty factors and historical perspective on the reliance on quantitative data to develop values for inter- and intraspecies extrapolation. The course will focus on the IPCS methodology for CSAF development, including the thinking process and steps used for evaluating data. Examples and classroom activities will be used as instructional aids. Course Overview and Goals:
Dr. Lynne Haber has 14 years of experience in developing human health risk values for a variety of government agencies and private sponsors, and in research related to risk assessment methods. She is the Research Program Manager at Toxicology Excellence for Risk Assessment (TERA). Her interests include the improved use of mechanistic data in risk assessment, including incorporation of mode of action data in cancer risk assessment, and use of data to replace default uncertainty factors. She has been the lead author, coauthor, or reviewer of dozens of detailed assessment documents. She has served as a panel chairperson or panel member for scientific peer reviews organized by TERA, EPA, and other U.S. and foreign government agencies. She has also served on two panels for the NAS/NRC. Lynne is active in communicating her findings to the broader scientific community through participation in professional societies, teaching courses in risk assessment methods, routine publication of her work, service as an editorial reviewer for scientific journals, and through presentation of invited lecturers. Her published work includes lead authorship of the chapter on noncancer risk assessment (including dose-response modeling methods) for Patty’s Toxicology, and an invited review on the use of mechanistic data in risk assessment. She was also the coauthor for an analysis of the effect of genetic polymorphisms on human variability in dose, using PBPK and Monte Carlo modeling. She has published on methods for deriving occupational exposure limits, and on incorporating toxicokinetic data into risk assessment. She served as vice president and councilor of the SRA Dose-Response specialty group, is a Diplomate of the American Board of Toxicology, and is an officer of the SOT Risk Assessment Specialty Section (RASS). Bette Meek is the Manager of the Existing Substances Division in the Environmental Health Directorate of Health Canada. Her responsibilities involve hazard and risk assessment for chemical contaminants in the general environment. She is also primarily responsible for the approach to assessment of health effects of Existing Substances under the Canadian Environmental Protection Act. She has considerable experience in the evaluation of health-related data for the derivation of guidelines for chemical contaminants of air and drinking water. She has acted on numerous occasions as advisor in this area to international organizations (including the World Health Organization, the Organization for Economic Cooperation and Development and the International Labour Organization), including in the development of the CSAF methodology. Ms. Meek graduated with an Honours B.Sc. in Biology from Queen's University and an M.Sc. in Toxicology (with Distinction) from the University of Surrey in the U.K, and has authored over 90 publications on risk assessment of environmental contaminants. Dr. John C. Lipscomb has a career (so far) spanning 21 years of service in the U.S. government including service to the U.S. Food and Drug Administration, U.S. Air Force and U.S. Environmental Protection Agency. He received a PhD degree in Interdisciplinary Toxicology from the University of Arkansas for Medical Sciences in 1991 and certification in General Toxicology (DABT) from the American Board of Toxicology in 1995. He is presently employed in the US EPA’s Office of Research and Development, National Center for Environmental Assessment (Cincinnati, OH) where he develops risk assessment guidance, technical assessments and provides advice to chemical managers considering pharmacokinetic analyses for their assigned chemicals. He is well-published in the areas of chemical metabolism, toxicology, pharmacokinetics and risk assessment. His work has been recognized with awards of merit and commendation medals from the Air Force, Army, EPA, and the National Institute for Occupational Safety and Health. He serves as an ad hoc reviewer for multiple journals and is on the editorial boards for Toxicological Sciences and Toxicology Mechanisms and Methods. His interests include continuing to improve the scientific basis for human health risk assessment. He has developed and provided guidance to risk assessors through publication in the open scientific literature and by co-authoring several EPA guidance documents. His work with the chemical manager was instrumental in replacing the default values for toxicokinetic uncertainty in the oral reference dose for boron and compounds, which is a precedent-setting assessment for the US EPA. He has and continues to provide service to the risk assessment and toxicology communities through active support of the Spring Toxicology and Risk Assessment Conference held annually near Wright-Patterson Air Force Base Ohio; he is a past president of the Ohio Valley chapter of the Society of Toxicology, the Dose-Response Specialty Group of SRA and he presently serves as the President of the Ohio Chapter, SRA. The pre-registration fee is $175. On-site registration is $205. You do not need to register for the Annual Meeting to attend the workshop. Registration will be handled by Secretariat sra@burkinc.com PRE-REGISTRATION DEADLINE IS NOVEMBER 4, 2005 Venue
The event will be held on Sunday, 4 December 2005, at Wyndham
Palace Resort & Spa More Information
More information can be obtained from Dr. Lynne Haber haber@tera.org, telephone 513-542-7475 ext. 17, fax 513-542-7487.
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Last updated: 01/03/2007