US-EPA approach

In 1988, the US-EPA adopted the ADI approach in its regulatory measures against environmental pollution with a number of modifications (US-EPA 1988, 1993). Instead of the terms ADI and safety factor, the terms Reference Dose (RfD) and uncertainty factor (UF), respectively, were selected. The RfD is derived from the NOAEL by dividing by the overall UF. The overall UF originally suggested and reconfirmed in 2002 (US-EPA 2002) generally consists of a 10-fold factor for each of the following  

According to US-EPA (1993), the first four of the above-mentioned factors are adapted from Dourson and Stara (1983). 

It is also noted that there is overlap in the individual UFs and that the application of five UFs of ten for the chronic reference value (yielding a total UF of 100,000) is inappropriate. In fact, in cases where maximum uncertainty exists in all five areas, it is unlikely that the database is sufficient to derive a reference value. Uncertainty in four areas may also indicate that the database is insufficient to derive a reference value. In the case of the RfC, the maximum UF would be 3,000, whereas the maximum would be 10,000 for the RfD. This is because the derivation of RfCs and RfDs has evolved somewhat differently. The RfC methodology (US-EPA 1994) recommends dividing the interspecies UF in half, one-half (10° ) each for toxicokinetic and toxicodynamic considerations, and it includes a Dosimetric Adjustment Factor (D AF, represents a multiplicative factor used to adjust an observed exposure concentration in a particular laboratory species to an exposure concentration for humans that would be associated with the same delivered dose) to account for toxicokinetic differences in calculating the Human Equivalent Concentration (HEC), thus reducing the interspecies UF to 3 for toxicodynamic issues. RfDs, however, do not incorporate a DAF for deriving a Human Equivalent Dose (HED), and the interspecies UF of 10 is typically applied, see also Section 5.3.4. It is recommended to limit the total UF applied for any particular chemical to no more than 3000, for both RfDs and RfCs, and avoiding the derivation of a reference value that involves application of the full 10-fold UF in four or more areas of extrapolation. 

In addition, a modifying factor (MF) could be applied (US-EPA 1993). The MF is in reality an additional UF that is greater than 0 and less than or equal to 10 the default value is 1. The MF should account for uncertainties of the study and database not explicitly handled by the use of the general UFs e.g., the completeness of the overall database and the number of species tested. In the 2002 review of the RfD and RfC processes (US-EPA 2002), it was recommended that use of the MF be discontinued as it was considered that the uncertainties accounted for by the MF is sufficiently accounted for by the general UF. 

The US-EPA staff paper from 2004 titled An Examination of EPA Risk Assessment Principles and Practices (US-EPA 2004) provides comprehensive and detailed information on the 

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We direct attention to procedures for estimating the air quality impact of stationary sources based on an approach developed by the US EPA. 

Below we describe three examples of frameworks that use the Best in Class approach including another US EPA DfE Program called the Formulator Program, the CleanCredients database and SC Johnson s GreenList . 

Other ways to minimize matrix effects include improving the sample cleanup, diluting the sample, using labeled internal standards, using standard addition, or using matrix-matched standards. The last approach, however, is not permitted for enforcement methods at present by the US EPA or the US Pood and Drug Administration... 

Since the first description of the BMD approach in health risk assessment of chemicals, the method has been modified and extended by many others. Central in this work was a workshop organized by the International Life Science Institute (ILSl) and reported in Barnes et al. (1995) and a workshop organized by the US-EPA Risk Assessment Eomm resulting in a US-EPA report (US-EPA 1995). No consensus was reached at these workshops on which variation and extension of the BMD approach is most appropriate for the use in human health risk assessment. 

Internationally, the BMD approach is used by the US-EPA to derive health-based limit values (US-EPA 2007a). Within the OECD (OECD 2000) and the European Union (EC 2003), the BMD approach is also mentioned as an alternative to the traditional NOAEL approach in health risk assessment but is not implemented in regulatory toxicology within the European Union. 

US-EPA. 1995. The use of the benchmark dose approach in health risk assessment. US Environmental Protection Agency (EPA), Office of Research and Development, Doc. EPA/630/R-94/007, Washington, DC. 

The approach of deriving a tolerable intake by dividing the N/LOAEL, or alternatively a BMD for the critical effect(s) by an assessment factor has been described and discussed extensively in the scientihc literature. It is beyond the scope of this book to review all these references. This chapter presents an overview of pubhshed extrapolation methods for the derivation of a tolerable intake based on the assessment factor approach, i.e., limited to address effects with threshold characteristics, and is not meant to be exhaustive. The main focus is on the rationale for and the use of the assessment factors. Pertinent guidance documents and reviews for the issues addressed in this chapter include WHO/IPCS (1994, 1996, 1999), US-EPA (2002, 2004), IGHRC (2003), ECETOC (2003), KEMI (2003), Kalberlah and Schneider (1998), Vermeire et al. (1999), and Nielsen et al. (2005). 

The overlap of areas covered by the FQPA factor and those addressed by the traditional UFs was recognized, and it was concluded that the current UFs, if appropriately applied using the approaches recommended in the review (i.e., US-EPA 2002), will be adequate in most cases to cover concerns and uncertainties regarding the potential for pre- and postnatal toxicity and the completeness of the toxicology database. In other words, an additional UF is not needed in the RfC/RfD methodology because the currently available factors are considered sufficient to account for uncertainties in the database from which the reference values are derived (and it does not exclude the possibility that these UFs may be decreased or increased from the default value of 10). 

In 1988, the US-EPA adopted the ADI approach with respect to the derivation of RfDs and RfCs with a 10-fold UF to account for interspecies extrapolation (US-EPA 1988, 1993), see Section 5.2.1.1. It was noted, in the 2002 review of the RfD and RfC processes (US-EPA 2002), that the interspecies UF is generally presumed to include both toxicokinetic and toxicodynamic aspects. 

Baird et al. (1996) suggested a probabilistic alternative to the practice used by the US-EPA to derive RfDs from a NOAEL and application of UFs. The probabilistic approach expresses the human population threshold for a given substance as a probability distribution of values, rather than a single RfD value, taking into account the major sources of scientific uncertainty in such estimates. The approach was illustrated by using much of the same data that US-EPA used to justify their RfD procedure. For the four key extrapolations that were considered necessary to define the human population threshold based on animal data (interspecies, interindividual, LOAEL-to-NOAEL, and subchronic-to-chronic), the proposed approach used available data to define a probability distribution of each adjustment factor, rather than using available data to define point estimates of UFs. 

The quantitative dose-response assessment involves two different challenges, namely to determine the relationship between doses and the frequency of cases of cancer (i.e., potency evaluation), and to determine what statistical risk is tolerable or acceptable. This section gives a very short overview of some general aspects related to the quantitative dose-response assessment. The currently used approach by the WHO, the US-EPA, and the EU, as well as new approaches for the risk assessment of compounds that are both genotoxic and carcinogenic, are presented in Sections 6.3 and 6.4, respectively. 

The most widely used of the many mathematical models proposed for extrapolation of carcinogenicity data from animal studies to low-dose human exposures (i.e., low-dose extrapolation) is the LMS model. This has, in effect, become the default approach for quantitative risk assessment and has been used by, e.g., the US-EPA for many years as well as by the WHO in relation to derivation of drinking-water guideline values for potential carcinogens (WHO 1996) (see Section 9.2.1.2 for drinking-water guideline values). 

The US-EPA has in its 1996 Proposed Guidelines for Carcinogen Risk Assessment (US-EPA 1996) adopted the dose descriptor LEDio (the 95% lower confidence limit on a dose associated with a 10% extra tumor risk) whereas in its 2005 Guidelines for Carcinogen Risk Assessment (US-EPA 2005), no defined incidence has been recommended (see Section 6.3.2). Within the EU chemical s regulation, the dose descriptor T25 has been proposed (see Section 6.3.3). In the newly proposed MOE approach, the JECFA and the EFSA have recommended the dose descriptor BMDLio (see Section 6.4). 

In 1996, the US-EPA published their Proposed Guidelines for Carcinogen Risk Assessment (US-EPA 1996). These Proposed Guidelines were a revision of the 1986 Guidelines for Carcinogen Risk Assessment (US-EPA 1986) and introduced, among others, a new approach for the quantitative risk assessment. A revised draft Guidelines was launched in 1999 (US-EPA 1999) and the final version was published in 2005 (US-EPA 2005). 

The following overview of the US-EPA revised quantitative approach for cancer risk assessment is based on the final version of the Guidelines for Carcinogen Risk Assessment (US-EPA 2005). 

The US-EPA s Office of Pollution Prevention and Toxics (OPPT) uses a tiered approach to exposure assessment (US-EPA 2007a). Exposure assessments may use measured data or model estimates. Representative measured data of known quahty are preferred over model estimates and are needed to vahdate and improve models. The US-EPA Guidelines for Exposure Assessment... 

The TGD does not suggest default reference values for feed or water intake with the explanation that experimental conditions (e.g., type of diet) may affect the water and feed consumption. Instead aUometric equations are provided in order to derive default values on a case-by-case basis. The aUometric equations have been divided into species-specific equations, see Table 7.16, and general equations, see Table 7.17. The aUometric equations were originally presented in a report published by the US-EPA (1988), see Section 7.4.2. The TGD recommends that where possible the equations that are species-specific should be applied as they represent the most realistic approach, although they do not always correlate weU. 

This section gives a short overview of the currently used risk characterization approaches in the WHO, the US-EPA, and the EU. 

Factorial designs, in which n chemicals are tested at x dose levels (x treatment groups) have been suggested by the US-EPA (US-EPA 1986) as a statistical approach for risk assessment of chemical mixmres. A 2 factorial design has been used to describe interactions between the carcinogenic activity of five polycyclic aromatic hydrocarbons at two dose levels (Nesnow 1994) and a 5 design to identify nonadditive effects of three chemicals on developmental toxicity at five dose levels (Narotsky et al. 1995). 

Various approaches have been suggested in the scientific literature for use in the evaluation of the health risks from exposure to mixtures of chemicals. Most attention and effort has been devoted to procedures to assess cumulative effects of exposure to chemicals that act by a similar mechanism/mode of action (US-EPA 2000a), in which case the concept of dose addition applies. 

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