Tolerable intake calculation

The tolerable intake (TI) is calculated by dividing the NOAEL (or LOAEL) for the critical effect(s) by the derived overall assessment factor (AF) ... 

The outcome of low-dose extrapolation is the resulting lifetime cancer risk associated with estimated exposure for a particular population. A wide range of models have been developed for low-dose extrapolation of animal data to calculate a tolerable intake for an acceptable risk, often set at one extra cancer per million exposed persons (see Section 6.2.4 for acceptable risk). 

A Tolerable Intake has been derived for this substance, based on a Benchmark Dose calculated for non-neoplastic renal effects in animals and an uncertainty factor. A Tolerable Intake is the... 

Several aspects of the problem of herbicides being contaminated with nitrosamines, and the resulting inadvertent introduction of nitrosamines into the environment, will be discussed in other papers in this symposium. Unrecognized until less than five years ago, the situation has inspired intense debate and prompted several of the environmental chemistry studies mentioned in this paper. Like the presumed threat from the in vivo nitros-ation of pesticide residues, discussions sometimes lack the type of anticipated dose and effect calculations just mentioned. Unlike the active ingredients, whose benefits can justify residue tolerances and acceptable daily intakes, nitrosamine contaminents afford no known benefits, and the desirability of minimizing their levels is undisputed. 

Based on the calculated Maximum Dietary Exposure (MDE) of PAEs, and the Non Observed Adverse Effect Level (NOAEL) calculated from the available toxicology evidence, mainly hepatic, renal changes and reproductive toxicity in animals [88, 89,130-133], and making an uncertainty factor between 100 and 200, the EFSA panel calculated the Tolerable Daily Intake (TDI) for DBP, BBP, DEHP,... 

Table 4 Estimated daily intakes (EDI) of phthalates based on the geometric mean values for urinary metabolites estimated by David [137] for CDC data measured in 289 US individuals [138] and the tolerable daily intake (TDI) values calculated by EFSA [62], CSTEE [134], and MHLW [68], as well as the reference dose of phthalates (RfD) calculated by EPA [136] (in pg/kg b.w./day)...

For threshold effects, a Tolerable Daily Intake (TDI) is calculated by dividing the NOAEL (or LOAEL) for the critical effect(s) with an overall UF. The current practice according to the D-EPA in relation to the setting of quality criteria for chemical substances in soil, drinking water, and ambient air is to divide the overall UF into three categories (D-EPA 2006) ... 

With respect to veterinary medicines, the US-FDA establishes tolerances to include a safety factor to assure that the drug will have no harmful effects on consumers of the food product. The US-FDA first determines the level at which the dmg does not produce any measurable effect in laboratory animals. From this, the US-FDA determines an acceptable daily intake (ADI), and the drug tolerance and withdrawal times are then determined so that the concentrations of dmg residues in edible tissues are below the ADI. Depending on the dmg, safety factors of between 100-fold to 2000-fold are included in the calculations used to set the tolerances. 

The NOAEL, LOAEL or BMD approach can be used to calculate a guidance or reference level of exposure below which no adverse effects above background would be expected. These guidance levels include reference dose (RfD), acceptable daily intake (ADI) and tolerable daily intake (TDI). 

Some critical differences in risk assessment procedure lead to confusing situations on a worldwide basis. These differences are due to some very controversial areas of safety issues including the calculation of the acceptable daily intake (ADI), the assignment of the ADI to maximum residue limit (MRL)/tolerance, the validation of the analytical methods needed to regulate drug residues, and the fitness of legislation to toxicology. 

In Tab. 10-1 the calculated number of samples n required is demonstrated for probabilities of an error of the first kind of a = 0.1 and a = 0.25. With the exception of cadmium and lead the number of samples required is less than or equal to 10 for a probability of an error of the first kind of 25%. When the intake is well below the provisional tolerable weekly maximum, as in the case investigated [HAHN et al., 1992], the sample size for representative assessment can be reduced considerably. 

When calculating chronic dietary exposure, the deterministic models use point values for both food consumption and residue concentration, thereby yielding a point estimate of dietary exposure. In the US, the initial chronic dietary exposure estimate is the Theoretical Maximum Residue Contribution (TMRC) and is analogous to the Theoretical Maximum Daily Intake (TMDI) used to estimate chronic dietary exposure in the EU. Both the TMRC and the TMDI are relatively conservative estimates of dietary expostire. The TMRC is calculated as the product of the mean consumption value and the US pesticide tolerance [6]. In the EU, the TMDI is calculated as the product of the mean consumption value and the Maximum Residue Limit (MRL) [7]. The objective of both calculations is essentially identical to calculate an estimate of the central tendency of the dietary exposure. Both calculated values use the central tendency dietary exposure estimate as the estimate of chronic (long-term) dietary exposure and calculate it using mean consumption data and the maximum residue permitted on the commodity. 

For chemicals such as food additives, food contaminants, and industrial chemicals the threshold, that is the dose at which toxic effects become apparent, is determined from the dose-response graph and used in the risk assessment process. The threshold value is used, together with safety factors, to determine the acceptable daily intake (ADI) of a food additive, or the tolerable daily intake (TDI) of a food contaminant, or the threshold limit value (TLV in the USA, or maximum exposure limit (MEL) in the UK), for an industrial chemical (see box for calculation). For a drug, information about the dose in animals below which there are no adverse effects will be necessary before human volunteers can be exposed in clinical trials. More extensive safety evaluation is carried out for drugs than for... 

Tolerable daily intake (TDI) an estimate of the daily intake of a substance (a food contaminant) over a lifetime that is considered to be without appreciable health risk. It is calculated in the same way as the ADI. 

For the Swedish population in the study, Oskarsson et al. (1996) reports that there was an efficient transfer of inorganic mercury from blood to breast milk and that mercury from amalgam fillings was probably the main source of mercury in breast milk, while methylmercury levels in blood did not appear to be efficiently transferred to breast milk. Exposure of the infant to mercury in breast milk was calculated to range up to 0.3 g/kg/day of which approximately one-half was inorganic mercury. This exposure corresponds to approximately one-half the tolerable daily intake of total mercury for adults recommended by the World Health organization. The authors concluded that efforts should be made to decrease total mercury burden in women of reproductive age Oskarsson et al. (1996). 

Risks associated with the ingestion of contaminated dust have been estimated by Butte and Heinzow [85] using the chronic oral reference dose available from the US-EPA Integrated Risk Assessment Information Service [156]. With a focus on small children (age 1-6 years, mean body weight 16 kg) and a daily intake of 100 mg house dust [24,83] tentative benchmarks for house dust were calculated. The assessment indicated for chlorpyrifos, DDT and diazinon that the tolerable exposure concentration in house dust might be exceeded in some samples and chlorpyrifos especially can be considered a potential hazard to householders. 

In 1954, the Food and Drug Administration published a paper that defined the basis for the acceptable daily intake (ADI). The ADI was a threshold for intake of a chemical for a large population, below which there should be no significant toxic risks. The paper not only defined a procedure for the ADI, but also described the use of safety factors and how animal data could be used to estimate risk to humans. A no effect level was determined from animal studies and a safety factor of 100 was used to establish a safe level. Tolerances for chemical additives and pesticides were calculated, comparing the safe level to the residue concentration of these chemicals in crops (e.g., wheat) and that crop s contribution to the individual s daily diet. 

Vyskocil and Viau (1999) assessed molybdenum toxicity in humans and calculated the tolerable daily intake (TDl), no observed adverse effect level (NOAEL) and the lowest observed adverse effect level (LOAEL) for molybdenum intake. The authors have calculated a TDI of 0.009 mg Mo/kg/day and a NOAEL and LOAEL of 0.9 and... 

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