Assessment factors specification development

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 (1994, 1996, 1999) did not consider an extrapolation factor for duration of exposure specifically, but the uncertainty related to this element is included in a broader defined additional factor addressing the adequacy of the overall database (Section 5.9). The US-EPA (1993) has adopted the 10-fold factor to account for the uncertainty involved in extrapolating from less than chronic NOAELs to chronic NOAELs. This default value has later on been reconfirmed (US-EPA 2002) when only a subchronic duration smdy is available to develop a chronic reference value no chronic reference value is derived if neither a subchronic nor a chronic smdy is available. For systemic effects, ECETOC (2001) recommended a default assessment factor of 6 for extrapolation from subacute (28 days) to chronic exposure, and a factor of 2 from subchronic (90 days) to chronic exposure. For local effects, no additional assessment factor is needed for duration of exposure extrapolation for substances with a local effect below the threshold of cytotoxicity. KEMl (2003) suggested that extrapolation from subchronic to chronic exposure should be based on the distribution of NOAEL ratios reported by Vermeire et al. (2001) with an assessment factor of 16 covering 95% of the substances compared and for extrapolation from subacute to chronic exposure, with an assessment factor of 39 covering 95% of the substances. 

These correction factors have not been directly applied to other foods, but it would be prudent to test for the presence of interfering substances, in particular sugars and ascorbate in fresh fruits, and to assess their level of interference i n the assay. Correction factors for other interferences may need to be specifically developed. 

The DCS is a more specific tool to help drug developers make risk decisions concerning potential pharmaceutical candidates (Figure 1) (Dressman et al., 2001 Sun et al., 2004). These factors are assessed across the development spectra... 

The nurse should assess how the client has been controlling his HTN and ask specifically about erectile dysfunction related to hypertensive medication. HTN is a risk factor for developing other cardiovascular diseases, including stroke. This client has two risk factors for developing a stroke HTN and his racial background. 

Fluor Daniel Inc. has developed data that it applies to a wide spectrum of industry applications. This data is updated and tailored for specific use requirements necessary to perform risk and availability assessments. Maintenance and operational factors are assessed and incorporated for specific uses. 

A large number of considerations and factors must be entertained for the conception, development, preparation, assessment, characterization, and certification of RMs, including (a) end use requirements, (b) selection of materials, (c) preparation, (d) physical characterization, (e) chemical characterization, (f) certification, (g) documentation, and (h) distribution. Most of these have an overwhelming impact on the finally developed RM and on its credibility. This section deals with the steps, collectively denoted as collection and preparation, occurring early in the scheme of RM development. It treats general collection and preparation principles, and provides specific examples of preparative procedures. 

A specific immunoassay for measuring two-chain factor VIIa levels in plasma has been developed to identify activation of factor VII in patients with acute coronary syndromes suchs as myocardial infarction and unstable angina (12). Because regulation of factor VIIa is believed to be mediated by tissue factor pathway inhibitor (TFPI), its measurement is also useful in assessing thombotic and cardio-vasular disorders. Because TFPI is released by heparin, its measurement is also useful in assessing the efficacy of heparin and endothelial cell function (93). 

In the case of noncarcinogenic substances, there exists a threshold this is an exposure with a dose below which there would not be adverse effect on the population that is exposed. This is the reference dose (RfD), and it is defined as the daily exposure of a human population without appreciable effects during a lifetime. The RfD value is calculated by dividing the no observed effect level (NOEL) by uncertainty factors. When NOEL is unknown, the lowest observed effect level (LOEL) is used. NOEL and LOEL are usually obtained in animal studies. The main uncertainty factor, usually tenfold, used to calculate the RfD are the following the variations in interspecies (from animal test to human), presence of sensitive individuals (child and old people), extrapolation from subchronic to chronic, and the use of LOEL instead of NOEL. Noncancer risk is assessed through the comparison of the dose exposed calculated in the exposure assessment and the RfD. The quotient between both, called in some studies as hazard quotient, is commonly calculated (Eq. 2). According to this equation, population with quotient >1 will be at risk to develop some specific effect related to the contaminant of concern. 

There may be situations which warrant an assessment of carcinogenic potential, but immunogenicity and species specificity may preclude a two-year rodent bioassay. It may be necessary to develop in vitro assays to address a particular concern. For example, growth factors which may have the potential to support or stimulate the growth of transformed cells should be assessed for their ability to promote growth of either malignant or normal cells. 

The following considerations, when applied during method development, are likely to produce more robust, reliable, and transferable methods (a) the concerns of the customer (user) are considered in advance, (b) key process input variables are identified, (c) criticaTto-quality factors are determined, (d) several method verification tests are installed, (e) proactive evaluation of method performance during development is performed, (f) continuous customer involvement and focus are institutionalized, and (g) method capability assessment (suitability to be applied for release testing against specification limits) is established. 

The concept that infants and children may be a sensitive subgroup relates to their relative immaturity compared to adults. Children, as well as the unborn child, have in some cases appeared to be uniquely vulnerable to toxic effects of chemicals because periods of rapid growth and development render them more susceptible to some specific toxic effects when compared to adults. In addition to such toxicodynamic factors, differences in toxicokinetics may contribute to an increased susceptibility during these periods. It should be noted, however, that during the developmental and maturational periods the susceptibility to exposure to xenobiotics in children may be higher, equal, or even lower than in adults. Except for a few specific substances, not very much is known about whether and why the response to a substance may differ between age groups. It should also be borne in mind that, in terms of risk assessment, children are not simply small adults, but rather a unique population (Nielsen et al. 2001). 

US-EPA. 2006. Child Specific Exposure Factors Handbook 2006 (External Review Draft). Washington, DC National Center for Environmental Assessment. Office of Research and Development. Presently undergoing update (In press), http //cfpub.epa.gov/ncea/cfm/recordisplay.cfm7deid = 56747 US-EPA. 2007a. EPA/OPPT Exposure Assessment Tools and Models website, http //www.epa. gov/opptintr/ exposure /pub s/opptexpo. htm... 

---