The no observed adverse effect level

An important parameter in the risk assessment of hazardous wastes is the no-efifect level to which a population may be exposed. This level, defined as the no observed effect level (NOEL), is difificult to measure and also difficult to define accimately. Its values are based on epidemiological data and controlled animal experiments designed to determine the highest dose that will not produce an adverse effect. The no observed adverse effect level (NOAEL) is a variant of the NOEL in that it classifies only toxicological effects. Other measures related to the NOEL and the NOAEL are the LOEL lowest observed effect level) and LOAEL lowest observed adverse effect level), a stricter version of the LOEL. 

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MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor approach. They are below levels that might cause adverse health effects in the people most sensitive to such chemical-induced effects. MRLs are derived for acute (1-14 days), intermediate (15-364 days), and chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the liver or kidneys, or birth defects) are not used as a basis for establishing MRLs. Exposure to a level above the MRL does not mean that adverse health effects will occur. 

Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during a lifetime. The RfD is operationally derived from the No-Observed-Adverse-Effect Level (NOAEL- from animal and human studies) by a consistent application of uncertainty factors... 

MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor approach. They are below levels that might cause adverse health effects in the people most sensitive to such chemical-induced effects. MRLs are derived for acute (1-14 days), intermediate (15-364 days), and chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. 

To calculate the safe re-entry interval (REI), the margin of exposure (MOE) must be considered. Worker risk is measured as a margin of exposure and is related to how closely the occupational exposure comes to the no observed adverse effect level (NOAEL, for oxamyl 50 mg kg day ). MOE is defined as... 

The no observed adverse effect level (NOAEL) is obtained from the most relevant toxicity study. The lowest NOAEL observed on the toxicology studies was 1.5 mg/kg/day based on reduced weight gain in a 2-year chronic feeding study in rats. An estimate of no more than 30 days of use or handling per year was used in the calculation of the U.S. EPA safety factors. 

For most chemicals, actual human toxicity data are not available or critical information on exposure is lacking, so toxicity data from studies conducted in laboratory animals are extrapolated to estimate the potential toxicity in humans. Such extrapolation requires experienced scientific judgment. The toxicity data from animal species most representative of humans in terms of pharmacodynamic and pharmacokinetic properties are used for determining AEGLs. If data are not available on the species that best represents humans, the data from the most sensitive animal species are used to set AEGLs. Uncertainty factors are commonly used when animal data are used to estimate minimal risk levels for humans. The magnitude of uncertainty factors depends on the quality of the animal data used to determine the no-observed-adverse-effect level (NOAEL) and the mode of action of the substance in question. When available, pharmocokinetic data on tissue doses are considered for interspecies extrapolation. 

For many substances the body s own mechanisms for de-toxification and repair mean that low doses of some chemicals can be tolerated without experiencing any adverse effects. However, once a certain threshold has been exceeded then the degree of adverse effect is related to the dose. The highest dose at which no adverse effects are observed in the most susceptible animal species is identified as the No Observed Adverse Effect Level (NOAEL). The NOAEL is used as the basis for setting human safety standards for food additive Acceptable Daily Intakes (ADIs)4... 

Determine the no observed adverse effect level (NOAEL) in animals— the highest dose level that does not produce a significant increase in adverse effects. 

As has been emphasized so many times in the preceding chapters, these various manifestations of toxicity all display dose-response characteristics, where by response we refer to the incidence or severity of specific adverse health effects. As we demonstrated in earlier chapters, toxic responses increase in incidence, in severity, and sometimes in both, as dose increases. Moreover, just below the range of doses over which adverse effects can be observed, there is usually evidence for a threshold dose, what we have called the no-observed adverse effect level (NOAEL). The threshold dose must be exceeded before adverse effects become observable (Chapter 3). Deriving from the literature on toxic hazards, descriptions of the dose-response relationships for those hazards comprise the dose-response assessment step of the four-step process. 

Ratio of the No-Observed-Adverse-Effect Level (NOAEL) for the critical effect to the theoretical, predicted, or estimated exposure dose or concentration. 

Hazard characterization, also known as dose-response assessment, is the second stage in hazard assessment, and the second step in the process of risk assessment. At this step, the No-Observed-Adverse-Effect Level (NOAEL) and the Lowest-Observed-Adverse-Effect Level (LOAEL) are derived for the observed effects, where possible and appropriate. 

For threshold effects, traditionally, a level of exposure below which it is believed that there are no adverse effects estimated, based on an approximation of the threshold termed the No-Observed-(Adverse)-Effect Level (NO(A)EL) and assessment factors this is addressed in detail in Chapter 5. This estimated level of exposure will in this book be termed tolerable exposure level. Examples, where this approach is used, include establishment of the Acceptable/Tolerable... 

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. 

As an example, Hsieh et al. identified toxicodynamic biomarkers in monkey semm that demonstrated a quantitative relationship with drug exposure (Cr iax, AUC) and related pathological events [148], The biomarkers were used for a more precise calculation of the no observed adverse effect level (NOAEL). The safety of three different dosing schedules was predicted using pharmacokinetic pharmacodynamic (PKPD) modeling and biomarker analysis. 

ChernoffN, Rogers EH, Gage MI et al (2008) The relationship of maternal and fetal toxicology hioassays with notes on the biological significance of the no observed adverse effect level . Reprod Toxicol 25 192-202... 

Dorato MA, Engelhardt JA (2005) The no-observed-adverse-effect-level in drug safety evaluation use, issues, and definition(s). Regul Toxicol Pharmacol 42 265-274... 

Maternal blood boron concentrations were elevated in all boron groups in a dose-dependent manner. On gestational day 20, blood B concentrations of 1.3 mg/kg FW were associated with the no-observed-adverse-effect level (NOAEL) and 1.53 mg/kg FW with the lowest-observed-adverse effect level (LOAEL), equivalent to dietary intakes of 10 and 13 mg B/kg BW daily, respectively, for developmental toxicity. Developmental toxicity persisted postnatally only at 25 mg B/kg BW daily, a dose associated with more than a 10-fold increase in maternal blood B (2.8 mg B/kg FW) vs. 0.23 mg/kg FW in controls (34)... 

The evaluation of dose-response relationships includes the identification of effective dose levels as well as doses that are associated with low or no increased incidence of adverse effects compared with controls. Many studies identify either the lowest dose causing an adverse effect (lowest-observed-adverse-effect level, or LOAEL) or the no-observed-adverse-effect level (NOAEL) (Calabrese Baldwin,... 

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