ECETOC approach

The approach recommended by the ECETOC (1995) is to derive the best scientific estimate of a Human No-Adverse-Effect Level, referred to in the report as the Predicted No-Adverse-Effect Level (PNAEL). The approach distinguishes three stages  

The scientifically derived adjustment factors include the following elements  

This approach discriminates factors to a large extent in order to distinguish between the single adjustments and to separate best estimates from uncertainty. It should be noted that the ECETOC approach does not mention the establishment of an overall factor and although they mention that all discriminated aspects introduce uncertainties, they do not give guidance on how to account for this. It could also be questioned here whether a nonscientific factor should be discussed in a scientific risk assessment. 

In a more recent report, ECETOC (2003) has further developed many of the principles established in the previous report (ECETOC 1995) and replaced the guidance provided therein on 

Similarly to the previous ECETOC approach, this revised approach does not mention the establishment of an overall factor. 

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A review made by ECETOC (European Centre for Ecotoxicology and Toxicology of Chemicals, an industry-financed scientific fomm) on the use of (Q)SARs within current regulatory decision-making frameworks in EU, North America, and Japan, and within industry concluded that applicability of currently available (Q)SARs for chronic mammalian toxicity, certainly as a stand-alone approach, was very limited at that time (ECETOC 2003). 

The Nordic group has questioned the ECETOC (2004) approach described in Section 4.13.4.1 ... 

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). 

In 1961, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the Joint Meeting of Experts on Pesticides Residues (JMPR) adopted this approach in a slightly modified form The safe level was called the Acceptable Daily Intake (ADI) and expressed in mg/kg body weight per day (Vermeire et al. 1999, ECETOC 2003). Usually, a safety factor of 100 is used by JECFA and JMPR for establishing ADIs by this ADI approach however, the procedures adopted by JECFA and JMPR do not generate a clear justification for deviation from the factor of 100, but in some individual cases, an expert explanation is given for the use of factors other than 100 (Vermeire et al. 1999). 

ECETOC (2003) recommended that in the absence of any substance- or species-specific mechanism or PBPK modeling (Section 4.3.6), allometric seating based on metabolic rate (W° ) (caloric requirement approach. Section 5.3.2.3) is considered to provide an appropriate default for an assessment factor for interspecies differences with respect to systemic effects. Allometric scaling was stated as being a tool for estimating interspecies differences of internal exposure or body burden and to provide indirectly information on differences in sensitivity between species. Typical scaling factors for interspecies adjustment were noted as 7 for mouse, 4 for rat, and 2 for dog however. 

ECETOC (2003) recommended that if an appropriate NOAEL is available, then no extrapolation and hence, no assessment factor is necessary. Where it is considered more appropriate to use the LOAEL, a default assessment factor of 3 was recommended however, the factor may need to be adjusted depending on the effects observed at the LOAEL and the slope of the dose-response curve. The BMD could be an alternative approach for defining or confirming a NOAEL depending on the data quality and dose spacing. 

The T25 approach was discussed at a workshop organized by the European Centre for the Ecotoxicologicy and Toxicology of Chemicals (ECETOC) (Roberts et al. 2001, ECETOC 2002). It was concluded that the use of the T25 method in risk assessment is problematic due to uncertainties arising from the false assumption of both precision and linearity in the dose-response curves for tumor induction. 

In vitro testing systems are most useful in two important areas. First, they are useful in screening for toxicity, particularly in cases where sufficient in vivo data exist to validate the in vitro results. Second, in vitro tests are useful to study mechanisms of toxicity, and frequently they represent the only available approach for such studies. The wide variety of in vitro systems available to the reproductive toxicologist has been reviewed extensively (e.g., ECETOC, 1989 Chapin Heindel, 1993 Heindel Chapin, 1993 OECD, 1996b Genschow et al., 2000). 

ECETOC (1989) Alternative approaches for the assessment of reproductive toxicity. Brussels, European Centre for Ecotoxicology and Toxicology of Chemicals (Monograph No. 12). 

Alternative Methods (ECVAM) confirmed and developed ECETOC s role as a key contributor to the development of sound scientific approaches to the safety assessment and consequential responsible environmental management of chemicals. 

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