Toxic equivalent dose

The use of desiccated thyroid rather than synthetic preparations is never justified, since the disadvantages of protein antigenicity, product instability, variable hormone concentrations, and difficulty in laboratory monitoring far outweigh the advantage of low cost. Significant amounts of T3 found in some thyroid extracts and liotrix may produce significant elevations in T3 levels and toxicity. Equivalent doses are 100 mg (1.5 g) of desiccated thyroid, 100 Mg of levothyroxine, and 37.5 ug of liothyronine. 

From this equation, it is apparent that the Total MOE is a dose (BMD(l)) with known toxicological characteristics divided by the total toxic equivalent dose (Total TED). Thus, despite the non-transparent form of the usual equation for... 

Probabilistic risk assessment methods are described herein for determining a popnlation s distribution of the dose from exposure and the combination of that exposnre characterization with appropriate toxicological information to form aggregate and cumulative risk assessments. An individual s dose from exposure is characterized as a set of chemical- and route-specific dose profiles over time. Toxic equivalence factors (TEFs) that reflect the toxic endpoint and exposure duration of concern are used to scale chemical- and route-specific doses to toxic equivalent doses (TEDs). The latter are combined in a temporally consistent manner to form a profile over time of the Total TED. For each individual, a Total MOE is calculated by dividing a toxicologically relevant benchmark dose (e.g. an EDio) by the individual s Total TED. The distribution of the Total MOE in a popnlation provides important information for risk management decisions. 

Exposure to specific PCB congeners, especially dioxin-like PCBs, has been linked to the increase in breast cancer risk (Demers et al. 2002). Smith (1997) assessed cancer potency of PCBs calculating the cancer slope factors (CSF) from animal data. The CSF for 60% chlorinated PCB was reported as 1.9 mg/kg/day and that of 54% and 42% chlorinated PCBs were less than 1.0 mg/kg/day. No correlation could be established between the toxic equivalent dose and the CSF for such chlorobiphenyls. 

Toxic equivalency factors (TEFs) are estimated relative to 2,3,7,8-TCDD, which is assigned a value of 1. They are measures of the toxicity of individual compounds relative to that of 2,3,7,8-TCDD. A variety of toxic indices, measured in vivo or in vitro, have been used to estimate TEFs, including reproductive effects (e.g., embryo toxicity in birds), immunotoxicity, and effects on organ weights. The degree of induction of P450 lAl is another measure from which estimations of TEF values have been made. The usual approach is to compare a dose-response curve for a test compound with that of the reference compound, 2,3,7,8-TCDD, and thereby establish the concentrations (or doses) that are required to elicit a standard response. The ratio of concentration of 2,3,7,8-TCDD to concentration of test chemical when both compounds produce the same degree of response is the TEF. Once determined, a TEF can be used to convert a concentration of a dioxin-like chemical found in an environmental sample to a toxic equivalent (TEQ). 

Extrapolation of data from studies in experimental animals to the human situation involves two steps a first step is to adjust the dose levels applied in the experimental animal studies to human equivalent dose levels, i.e., a correction for differences in body size between laboratory animals and humans. A second step involves the application of an assessment factor to compensate for uncertainties inherent in toxicity data as well as the mterspecies variation in biological susceptibility. These two steps are addressed in the following sections. 

This paradox between the lack of toxicity of pure histamine and the apparent toxicity of equivalent doses of histamine in spoiled fish could be explained by the existence of potentiators of histamine toxicity in spoiled fish. These potentiators would serve to lower the threshold dose of histamine necessary to elicit scombroid poisoning symptoms in humans. 

Cadaverine has been shown to have a similar effect on the oral toxicity of histamine in guinea pigs (25.). Weiss et al. (IJ.) showed that 180 mg of histamine was without effect when administered orally to humans, while Motil and Scrimshaw (14) did observe some toxic symptoms after oral administration of an equivalent dose of histamine with "wholesome tuna. 

Hepatic Nicotinic acid hepatotoxicity (including cholestatic jaundice) has occurred. Cases of severe hepatic toxicity, including fulminant hepatic necrosis, have occurred in patients who have substituted sustained-release nicotinic acid products for immediate-release nicotinic acid at equivalent doses. Monitor ALT prior to treatment, every 6 to 12 weeks during the first year, and periodically thereafter (approximately 6-month intervals). 

In male Wistar rats, coumarin, 3-methylcoumarin or 4-methylcoumarin was administered intraperitoneally at a single dose of 1.03 mmol/kg bw and rats were killed 24 h later. Coumarin produced histological evidence of centrilobular necrosis, while the methyl analogues were much less toxic at equivalent doses. In the same study, these compounds had the same order of cytotoxicity in isolated hepatocytes as that observed in vivo (Femyhough et al, 1994). 

The procedure involves converting oxon to thion toxicity equivalents by multiplying the oxon value by its relative toxicity (ED of thion r ED,.q of oxon) in Table I. The ED. value is the aermal dose in ug/cnr of total body surface which produces 50% inhibition of red cell ChE activity 72 hours after application. The total thion and oxon level is then divided by the thion toxicity equivalents and the factor is multiplied by the safe level established for thion in Table I. This procedure was conducted for the dislodgeable residues of parathion-paraoxon, methidathion-methidathion oxon, and azinphosmethyl-azinphosmethyl oxon. The safe levels for the total disloggeable residues were determined to be 0.06, 0.2 and 1.6 ug/cm, respectively, for... 

In a 14-day test on rats, using an equivalent dose of CQ which caused 100% mortality, FQ caused only about 7% mortality. The liver, and to a lesser extent the kidney, appeared to be the two main target organs. Phase I and Ha of clinical experiments confirmed the good tolerability of FQ and its lower toxicity compared with CQ. 

As already introduced in Chapter 1, a widely used application of CA is the toxic equivalence factor (TEF) concept for the assessment of mixtures of polychlorinated dioxins and furans (PCDDs/Fs) (Van den Berg et al. 2006). Under the additional assumption of parallel dose-response curves, doses of specific PCDD/F isomers are all expressed in terms of the dose of a reference chemical, 2,3,7,8-... 

Additivity and no interactions. Additivity concepts that explain a shared adverse effect across chemicals include dose or concentration addition, which assumes chemicals share a common toxic MOA, and RA, which assumes chemicals act by toxicologically (and thus also statistically) independent MOA. There is also a body of research on the use of statistical dose-response modeling of empirical data to examine the joint toxic action of defined mixtures where the claim is that MOA assumptions are not necessary (Gennings et al. 2005). Dose addition methods scale the component doses for relative toxicity and estimate risk using the total summed dose, for example, using relative potency factors (RPFs), toxicity equivalency factors (TEFs), or a hazard index (HI). In contrast, RA (also named independent action ) is... 

The CA concept uses the toxic unit (TU) or the toxicity equivalence factor (TEF), defined as the concentration of a chemical divided by a measure of its toxicity (e.g., EC50) to scale toxicities of different chemicals in a mixture. As a consequence, the CA concept assumes that each chemical in the mixture contributes to toxicity, even at concentrations below its no-effect concentrations. The IA or RA concept, on the other hand, follows a statistical concept of independent random events it sums the (probability of) effect caused by each chemical at its concentration in the mixture. In the case of IA, the only chemicals with concentrations above the no-effect concentration contribute to the toxicity of the mixture. The IA model requires an adequate model to describe the (full) dose-response curve, enabling a precise estimate of the effect expected at the concentration at which each individual chemical is present in the mixture. The concepts generally are used as the reference models when assessing mixture toxicity or investigating interactions of chemicals... 

When the Total MOE approach is used and toxic equivalent factors and doses computed, the BMDs should be comparable. Comparability is increased if all of the BMDs are for the same endpoint (or endpoints related to the common mechanism of action and of comparable severity). Comparability is also increased if the BMDs are all ED s (with the same ) as opposed to all NOAELs or all Lowest Observed Adverse Effect Levels (LOAELs), because the NOAELs and LOAELs are influenced by differences in experimental designs. Comparability is also increased if the BMDs all refer to the same species. 

Dose additivity It is assnmed that each chemical behaves as a concentration or dilntion of every other chemical in the Cumnlative Assessment Group (or chemical mixture). The response of the combination is the response expected from the eqnivalent dose of an index chemical. The equivalent dose is the sum of the component doses, scaled by each chemical s toxic potency relative to the index chemical (USEPA, 2002). 

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