Non-observable adverse effect level

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 3 Estimation of maximum dietary exposure (MDE) (95th percentile), non observed adverse effect level (NOAEL) and tolerable dally Intake (TDI) of the most used PAEs according to EFSA [62]...

Toxicity to humans was initially estimated to be 15 pg/person (mean value) based on the toxin content of the mussels from the blooms that originated the first two toxic episodes, 0.6 pg/g of meat (Killary Harbour) and 1.36 pg/g of meat (Arranmore) (equivalent to 0.15 and 0.4 monse nnits/g, respectively) (Ofuji et al. 1999b Satake et al. 1998a, 1998b). However, recent data showed that azaspiracid concentration is not reduced by heat (EU/SANCO 2001 Hess et al. 2005), which had been a parameter for initial calculations. Therefore, the lowest observed adverse effect level (LOEL) has been re-estimated to be within the range of 23 to 86 pg/person, with a mean valne of 51.7 pg/person (EU/SANCO 2001 FAO 2004). The non-observable adverse effect level (NOEL) was conseqnently calculated to be 80 pg/kg of shellfish meat, considering a safety factor of 3, which shonld account for individual variations, a maximum intake of 100 g per person and the lowest valne in the LOEL range. 

The slope of the dose-response curves is also an important characteristic, because it shows the development of the impact as a function of the increase of the dose the steeper the curve, the faster the therapeutic or toxic effects are reached. Another feature of the toxic effect is the foot point of the curve, the highest concentration where there was no toxic effect observed yet this is the level of the non-observable adverse effect level (or NOAEL no adverse effect level). The NOAEL values are directly influenced by the slopes of the curves materials with the same LD g values can yield very different NOAEL values (see the NOAEL values belonging to cmves in B and C). Sometimes, the so-called non-observable effect level (or NOEL no effect level) value is given, at which absolutely no impact can be measured. This is obviously smaller than the NOAEL value. The determination of the NOEL is usually very inaccurate. 

In the hazard assessment process, described in detail in Chapter 4, all effects observed are evaluated in terms of the type and severity (adverse or non-adverse), their dose-response relationship, and the relevance for humans of the effects observed in experimental animals. For threshold effects, a No- or a Lowest-Observed-Adverse-Effect Level (N/LOAEL), or alternatively a Benchmark Dose (BMD), is derived for every single effect in all the available smdies provided that data are sufficient for such an evaluation. In the last step of the hazard assessment for threshold effects, all this information is assessed in total in order to identify the critical effect(s) and to derive a NOAEL, or LOAEL, for the critical effect(s). 

Guidance values are developed from a standard such as, e.g., an Acceptable/Tolerable Daily Intake (ADI/TDI), and Reference Dose/Concentration (RfD/RfC). For threshold effects, the standard is derived by dividing the No-Observed-Adverse-Effect Level (NOAEL) or Lowest-Observed-Adverse-Effect Level (LOAEL), or alternatively a Benchmark Dose (BMD) for the critical effect (s) by an overall assessment factor, described in detail in Chapter 5. For non-threshold effects, the standard is derived by a quantitative assessment, described in detail in Chapter 6. 

Usually both sexes should be used in these studies, excluding non-human primates. The high dose should be above the no observed adverse effect level (NOAEL) but below a level inducing changes secondary to stress. Multiple dose levels are recommended in order to determine dose-response relationships and the dose at which no immunotoxicity is observed. 

N (or ri) NDIR NOAEL NOEL air exchange rate [h" ] non dispersive infra red no observed adverse effect level no observed effeet level... 

In this study, central nervous system function was evaluated in multiple tests including perceptual speed, simple reaction time, short-term memory, numerical ability, and manual dexterity. A lowest-observed- adverse-effect level (LOAEL) was seen in the same study when humans were exposed to 4,000 mg/m for 50 minutes. The subjects had a prolonged simple reaction time compared to control results in the same volunteers during a non-exposure period. It should be noted that because of practical constraints, these tests were conducted on volunteers at rest and that parallel pharmacokinetic studies have demonstrated greater uptake during exercise (Astrand et al. 1975). 

As we saw in chapter 7, toxicity factors used to evaluate non-cancer effects are primarily based on no-observed adverse effect levels (NOAELs) from animal studies. 

Non-toxic necines, 370 No observed adverse effect effect-levels (NOAEL), 2291-2292 Nootkatone, 2991, 3001 NO production, 2290 Noradrenaline, 588, 3709, 4068 NORA programme, 3541 Norbelladine, 484 Norbomane, 3472... 

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