Target organ toxicity dose

The HI method has been refined by the introduction of the target-organ toxicity dose (TTD) method. This method suggests that separate His should be estimated for all endpoints of concern. This imphes that a TTD should be established for all relevant endpoints for each chemical using the same principles as used in the normal derivation of the RfD/ADI/TDI and that HQs should be calculated for the relevant effects of each chemical (for details see ATSDR 2004). 

Apply target-organ toxicity dose (TTD, see Section 10.5.1.1) modification of the HI method for overlapping targets of toxicity or access any unique critical effect with separate HQ. 

Thyroid-Releasing Hormone Toxic Substances Control Act Thyroid Stimulating Hormone Treatment Technique Threshold of Toxicological Concern Target-organ Toxicity dose Unscheduled DNA Synthesis Uncertainty Factor United Nations... 

TABLE 21.4 Target Organ Toxicity Dose Calculation... 

Target Organ Toxicity Dose (TTD) A variant of the hazard index approach where effects for all components for all affected tissues. The target organ toxicity dose is summed regardless of whether they represent the critical effect or a secondary effect. Hazard index values are developed for each affected organ or system. 

Other refinements could be provided by implementing the target-organ toxicity dose approach, which attempts to estimate the plausible critical effect and IOC that would have been calculated had the particular mixture been tested (Mumtaz et al. 1994, 1997). This approach is complicated, and would be suggested only when additional assessment is needed, perhaps to resolve differences between expected and actual health effects outcomes, or where critical effects are different across constituents or fractions that make up the mixture. ... 

It is important to appreciate that the magnitude of the absorbed dose, the relative amounts of bio transformation product, and the distribution and elimination of metaboUtes and parent compound seen with a single exposure, may be modified by repeated exposures. For example, repeated exposure may enhance mechanisms responsible for biotransformation of the absorbed material, and thus modify the relative proportions of the metaboUtes and parent molecule, and thus the retention pattern of these materials. Clearly, this could influence the likelihood for target organ toxicity. Additionally, and particularly when there is a slow excretion rate, repeated exposures may increase the possibiUty for progressive loading of tissues and body fluids, and hence the potential for cumulative toxicity. 

In the absence of target organ toxicity with which to set the high dose at the maximally tolerated dose, the high dose can be set at the dose that produces an area under the curve (AUC). This is 25-fold higher than that obtained in human subjects. 

Thirteen-week toxicity studies of 2,2-bis(bromomethyl)propane-l,3-diol were conducted in male and female Fischer 344/N rats and B6C3Fi mice to determine target organ toxicity. 2,2-Bis(bromomethyl)propane-l,3-diol (technical grade, 78.6% pure) was administered by gavage in com oil for five days per week to rats, 6-7 weeks of age, at doses of 0, 50, 100, 200, 400 or 800 mg/kg bw and to mice, 6-9 weeks of age. 

Stochastic responses under conditions of the experiment should be reviewed carefully with respect to the relevance of the evidence to humans (e.g., the occurrence of bladder tumors in the presence of bladder stones and implantation site sarcomas). Interpretation of animal studies is aided by the review of target organ toxicity and other effects (e.g., changes in the immune and endocrine systems) that may be noted in pre-chronic or other toxicologic studies. Time- and dose-related incidence of pre-neoplastic lesions may also be helpful in interpreting animal studies. 

These cut-off values and consequent classifications should be applied equally and appropriately to both single- and repeated-dose target organ toxicants. 

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