The TTC concept should not be applied to carcinogens where adequate toxicity data are available from long-term studies and allow for a compound-specific risk assessment.

Identification methods for GTIs. GTIs can be identified by the following methods:

• Consulting a list of known genotoxins
• Determining whether an element has functional groups similar to those of known genotoxins
• Performing genotoxicity assays
• Using computer-based structure-activity relationship software programs (e.g., MultiCASE's Mcase, Accelrys's Topcat, or LHASA's DEREK)
• Performing Ames bacterial mutagenicity testing after software provides a structural alert. Results from the Ames test are considered more definitive than the in silico data.

Lou et al. reported a method-development strategy for the control of GTIs (9–11). Analytical techniques can be selected by dividing GTIs into two groups based on their volatility. High-performance liquid chromatography (HPLC) with UV detection should generally be the first choice for nonvolatile GTIs because of the methods' simplicity and availability (12). However, HPLC may not offer sufficient sensitivity for certain GTIs in low-level analysis. If GTIs offer insufficient UV response, ultraperformance or ultra fast liquid chromatography (UPLC or UFLC) can be used because they have enhanced UV-detector sensitivity. When GTIs lack chromophores, an evaporative light-scattering detector (ELSD) is the alternate choice. However, ELSD is limited in sensitivity and dynamic range. Refractive index detectors and fluorescence detectors are alternate detectors used in HPLC. Because low-quantitation limit establishment is challenging, coupling HPLC or UPLC with mass spectrometers (MS) significantly improves method sensitivity and speed (13, 14). These detectors are selective and minimize issues caused by interference in the sample matrix, thus improving data quality. However, these instruments are expensive and differ from vendor to vendor. Thus, transferring a method between the developing and receiving laboratories, which may use instruments from different vendors, requires optimization of multiple instrumental parameters (9).

Volatile GTIs, meanwhile, can be quantitated by gas chromatography (GC) with a flame ionization detector (FID) (14, 15). GC–FID in direct and headspace injection modes is generally the preferred method, but this depends on the properties of GTIs and sample matrices. An electron-capture detector (ECD) can be used when GTIs consist of halogens. Nitrogen–phosphorus detectors (NPD) offer an additional tool for GTIs containing nitrogen or phosphorus atoms. However, the applications of ECD and NPD are limited. GC–MS offers the most sensitive and selective detection and reduced background noise. The method also is less prone to interferences for low-level analysis of GTIs (16, 17). If the GTIs are labile, do not possess chromophores, and have reactive functional groups, they can be derivatized to form detectable species (e.g., hydrazine derivatizes with benzaldehyde to form 1,2-dibenzylidenehydrazine) (14, 18). The derivatization reagent should be selected according to the functional groups in the analyte. Derivatization helps in stabilization, incorporation of a unique structural moiety, enhancement of fluorescence, ionization for mass detection, and volatization for GC.