Enhanced Structure-Based, Tiered TTC Concept

Kroes et al. (2000, 2004) and Barlow (2005) combined the general TTC concept and the stmcture-based, tiered TTC concept to develop an enhanced stmcture-based, tiered TTC approach. 

Neurotoxicants, immunotoxicants, and teratogens were also further explored, and it was concluded that, except for the organophosphorous neurotoxicants, such compounds would be covered by the stmcmre-based, tiered TTC approach. For organophosphates, a human exposure threshold of 

18 jLg/person/day was derived. This threshold for organophosphates was not intended to replace the normal regulatory assessments and controls for organophosphates used as pesticides, but could be used to evaluate the risk should a nonapproved or unregulated organophosphate be detected as a contaminant in food. 

Specific considerations of metabolism and accumulation are not necessary in the application of a TTC provided that the substances are not likely to show very large species differences in accumulations such as, e.g., polyhalogenated-dibenzo-p-dioxins, dibenzofurans, and biphenyls and related compounds, as well as nonessential heavy metals in elemental, ionic or organic forms. Such substances are known to accumulate in the body, and the traditionally employed safety factors (Section 5.2.1) may not be high enough to account for species differences in rates of elimination of such chemicals. Therefore, the TTC approach should not be used for such substances. 

In addition, because it is still not known whether endocrine disrupters are active at very low exposures, it would be premature to include low-dose, endociine-mediated effects in the TTC approach. 

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