Chemical-Specific Assessment Factors

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. 

When appropriate chemical-specific data are available, a CSAF can be used to replace the relevant default sub-factor for example, suitable data defining the difference in target organ exposure in animals and humans could be used to derive a CSAF to replace the uncertainty sub-factor for animal to human differences in toxicokinetics (a factor of 4). The overall UF would then be the value obtained on multiplying the CS AF(s), used to replace default sub-factor(s), by the remaining default sub-factor(s) for which suitable data were not available. In this way, chemical-specific data in one area could be introduced quantitatively into the derivation of a tolerable intake, and data would replace uncertainty. 

Toxicological Risk Assessments of Chemicals A Practical Guide 

The WHO/IPCS (2005) guidance document describes the types and quality of data that could be used to derive a CSAF. The guidance is separated into four main sections covering each of the four different areas where CSAFs can be introduced to replace a default sub-factor  

The combination of adjustment factors and default UFs to derive an overall UF is also addressed. 

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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... 

Concern has been raised that infants and children are at higher risk than adults from exposure to environmental chemicals. The question of an extra assessment factor in the hazard and risk assessment for chemicals of concern for children has therefore been raised and the rationale for such a children-specific assessment factor has been discussed. 

In conclusion, the traditional assessment factors (interspecies, intraspecies, subchronic-to-chronic, LOAEL-to-NOAEL, and database-deficiency) are considered to cover the concerns and uncertainties for children adequately, i.e., no children-specific assessment factor is needed when setting tolerable intakes. However, it is recommended to perform children-specific risk assessments for chemical substances in products and foods intended for children, based on specific exposure assessments for children. 

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. 

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. 

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). 

The assessment factors generally apphed in the estabhshment of a tolerable intake from the NOAEL, or LOAEL, for the critical effect(s) are apphed in order to compensate for rmcertainties inherent to extrapolation of experimental animals data to a given human situation, and for rmcertainties in the toxicological database, i.e., in cases where the substance-specific knowledge required for risk assessment is not available. As a consequence of the variabihty in the extent and nature of different databases for chemical substances, the range of assessment factors apphed in the establishment of a tolerable intake has been wide (1-10,000), although a value of 100 has been used most often. An overview of different approaches in using assessment factors, historically and currently, is provided in Section 5.2. 

As mentioned earlier, the interspecies differences can be divided into differences in metabolic size (Section 5.3.2) and remaining species-specific differences. The average sensitivity of humans to the adverse effects of chemicals (after scaling for caloric requirement) is comparable to that of other species (KEMI 2003). However, an extra assessment factor is needed to account for the remaining... 

The question of an extra assessment factor in the hazard and risk assessment for chemicals of concern for children is specifically addressed in Section 5.2.1.13. The U.S. Food Quality Protection Act (FQPA) (US-EPA 1996) directed the US-EPA to apply an extra safety factor of 10 in assessing the risks of pesticides to infants and children. The US-EPA (2002) noted the overlap of areas covered by the FQPA factor and those addressed by the traditional UFs, and it was concluded that an additional UF (children-specific) is not needed in the setting of reference values because the currently available UFs (interspecies, intraspecies, LQAEL-to-NOAEL, subchronic-to-chronic, and database-deficiency) were considered sufficient to account for uncertainties in the database from which the reference values are derived. Renwick et al. (2000) concluded that the available data did not provide a scientific rationale for an additional 10-fold UF for infants and children and pointed out that when adequate reproduction, multigeneration, or developmental studies are conducted, there will be no need for an additional 10-fold factor. 

There is an emerging body of evidence that suggests person-to-person differences in exposure play an important role in the variability and uncertainty associated with risk assessments for chemicals (and other agents). The traditional or standard default approaches used in human health risk assessment often do not effectively evaluate interindividual variation and may underestimate the impact of chemical exposures on particular groups of individuals. Traditional approaches must be refined to adequately account for temporal variation in factors that contribute to complex aggregate exposure patterns (e.g., chemical-specific exposure media concentrations and time-activity interactions by humans) involving multiple, intermittent exposures. 

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