Lowest effect levels

The ratio between the estimated systemic exposure at the lowest effect level (or highest no-observed-effect-level NOEL) and the estimated systemic exposure at the anticipated therapeutic dosage level (the safety factor ). 

The distinction between non-adverse effects and adverse effects can seem academic, but is essential in the hazard assessment in relation to, e.g., evaluation of no-effect levels and lowest-effect levels (Section 4.2.4), identification of the critical effect(s) (Section 4.2.7), and to the magnitude of the assessment factor to be used for taking into account the uncertainty due to the nature and severity of effects (Section 5.8). 

As a consequence of the distinction between non-adverse effects and adverse effects, a tme No-Effect Level (NEL) and No-Adverse-Effect Level (NAEL) as well as a tme Lowest-Effect Level (LEL) and Lowest-Adverse-Effect Level (LAEL) exists in theory for a non-adverse effect and adverse effect, respectively. This is illustrated in Figure 4.6 where the NEL is the intersection of the dose-response curve with the x-axis, and the LEL, NAEL, and LAEL are somewhere on the dose-response curve. 

FIGURE 4.6 Dose-response curve illustrating the true no-effect level (NEL) and no-adverse-effect level (NAEL) as well as the true lowest-effect level (LEE) and lowest-adverse-effect level (LAEL). 

Female castration and primary ovarian failure - 1.25 mg/day cyclically. Adjust according to severity of symptoms and patient response. For maintenance, adjust to lowest effective level. 

Second and subsequent weeks Increase dosage to 50 mg 4 times daily. Maintenance Adjust dosage to lowest effective level. Twice daily dosage may be adequate. In a few resistant patients, up to 300 mg/day may be required for a significant antihypertensive effect. In such cases, consider a lower dosage of hydralazine combined with a thiazide or reserpine or a beta-blocker. However, when combining therapy, individual titration is essential to ensure the lowest possible therapeutic dose of each drug. 

Maintenance Keep dosage at the lowest effective level. Once an adequate response has been achieved, dosage may be gradually reduced depending on response. 

Effects seen, target organs in the mother, target organs of dys-morphology in fetuses, biomarkers of toxicity, no effect level, lowest effect level, etc. 

No effect dose level, lowest effect level and/or maximum tolerated dose level for maternal toxicity. 

The development of CSAFs may not always be possible or even necessary. For example, if the margin between the no- or lowest-effect level or bench mark concentration/bench mark dose (BMC/ BMD) and anticipated human exposure is very wide, the generation of the more sophisticated data necessary to replace part of a default UF would not warrant the necessary experimentation in animals and humans and the associated resource expenditure. However, where this margin is small, development of additional chemical-specific quantitative data may be justified to refine the dose-response analyses and scientific credibility of the outputs, such as ADIs, TDIs, margins of exposure, or margins of safety. 

USNRC regulations) LEL Lowest effect level, same as LOEL... 

BAT = Best Available Technology EPA = Environmental Protection Agency GC/MS = Gas Chromatogram/Mass Spectrometry LEC = Lowest Effect Level in literature (due to inadequate data to derive a... 

The direct effects of CPs in humans are limited to poorly documented clinical studies from the 1970s of the potential to induce irritation or sensitization of the skin following dermal application (reviewed in [5]). Based on the mammalian toxicity studies outlined above, the lowest effect level reported for CP is 5.7 mg/... 

Cardiac safety index (CSI) What is the ratio of the exposure (dose or concentration) where a signal is first apparent (lowest effect level, LOEL), compared with a projection or measured efficacious unbound plasma concentration (ED90, EC90) associated with an efficacious therapeutic dose Although ability to extrapolate nonclinical effects to humans is imprecise, a large CSI may provide a basis for reducing concern whereas a CSI <10 may increase concern about a particular... 

---