Chemical Specific Adjustment Factors

A recently pubhshed WHO/IPCS document regarding chemical-specific adjustment factors for interspecies differences and human variability (WHO/IPCS 2005) provides guidance for use of toxicokinetic data in dose-response assessment to develop the so-called Compound-Specific Assessment Factors (CSAFs) (Section 5.2.1.12). 

WHO/IPCS. 2005. Chemical-specific adjustment factors for interspecies differences and human variability Guidance document for use of data in dose/concentration-response assessment. Harmonization Project Document No. 2. http /whqlibdoc.who.int/publications/2005/9241546786 eng.pdf... 

A WHO/IPCS (2005) Harmonization Project Document has proposed using chemical-specific toxicological data instead of default assessment factors, when possible. The concept of Chemical-Specific Adjustment Factors (CS AFs) has been introduced to provide a method for the incorporation of quantitative data on interspecies differences or human variability in either toxicokinetics or toxicodynamics into the risk assessment procedure, by modifying the relevant default UF of 10. Incorporation of toxicokinetic or toxicodynamic data becomes possible if each factor of 10 is divided into appropriately weighted sub-factors as suggested by Renwick (1991, 1993) and adopted by WHO/IPCS (1994), see Section 5.2.1.3. 

IPCS (2001b) Guidance document for the use of data in development of chemical-specific adjustment factors (CSAFs) for interspecies differences and human variability in dose/ concentration-response assessment (draft). Prepared as part of the IPCS project on the Harmonization of Approaches to the Assessment of Risk from Exposure. Geneva, World Health Organization, International Programme on Chemical Safety. 

Meek ME, Renwick A, Ohanian E, Dourson M, Lake B, Naumann BD, Vu V (2002) Guidelines for application of chemical-specific adjustment factors in dose/concentration response assessment. Toxicology, 181-182 115-120. 

Division of benchmark doses and/or effect levels by default uncertainty factors represents the lower end of a continuum of increasingly data-informed approaches to estimation of hazard. For example, where additional adequate quantitative data on interspecies differences or human variability in either toxicokinetics or toxicodynamics (mode of action) are available, chemical-specific adjustment factors provide for their incorporation to replace appropriately weighted components of default uncertainty factors. This requires subdivision of default... 

Chemical-Specific Adjustment Factor (CSAF), Pages 530-533, Bette Meek SummaryPlus Full Text + Links PDF (84 K)... 

IPCS Guidance Document for the Use of Chemical-Specific Adjustment Factors (CSAF) for Interspecies Differences and Human Variability in Dose/Concentration-Response Assessment. 

See also Benchmark Dose Chemical-Specific Adjustment Factor (CSAF) Environmental Protection Agency, US International Programme on Chemical Safety Risk Assessment, Human Health Uncertainty Analysis. 

Chemical Specific Adjustment Factors (CSAFs) provide a consistent approach for incorporating mechanistic data to replace the default uncertainty factors for interspe-cies extrapolation and intraspecies variability (IPCS, 2001). This framework is based on early work by Renwick (1993) and applied by IPCS (1994), in which the default uncertainty factor of 10 for interspecies differences is divided into two factors of 2.5 and 4.0 for toxicodynamics and toxicokinetics, respectively. The default factor of 10 for infraspecies variability is similarly divided into two equal factors for toxicodynamics and toxicokinetics. Any one or all of these four subfactors can be replaced by chemical-specific data. The CSAFs have been used by the U.S. EPA in deriving an RfD for boron (U.S. EPA, 2004a) and by Health Canada in deriving a TC for 2-butoxyethanol (Health Canada, 2000). 

Benchmark Dose (BMD) modeling is an alternative method to the NOAEL/ LOAEL approach (Cmmp, 1984 Dourson et al., 1985 Barnes et al., 1995 U.S. EPA, 2000a). The method fits flexible mathematical models to the dose-response data and then determines the dose associated with a specified incidence of the adverse effects. Once this dose is estimated, then an RfD is estimated with the use of one or more uncertainty factors or Chemical Specific Adjustment Factors (CSAF) as described above. Advantages over the NOAEL/LOAEL approach include (1) the BMD is not limited to the tested doses (2) a BMD can be calculated even when the study does not identify a NOAEL and (3) unlike the NOAEL approach, the BMD approach accounts for the statistical power of the study. Numerous examples of BMD use in the dose-response assessment part of the risk assessment process are available on the U.S. EPA s Integrated Risk Information System (IRIS) (2004b). 

IPCS (International Programme on Chemical Safety), Guidance Document for the Use of Data in Development of Chemical-Specific Adjustment Factors (CSAF) for Interspecies Differences and Human Variability in Dose/Concentration Response Assessment, World Health Organization, Geneva, 2001. Available at http //www.ipcsharmonize.org (accessed October, 2004). 

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