NOAEL level

For the calculation of safety margins, the no observed adverse effect (NOAEL) level or no effect level (NOEL) should be defined. The reasons for the choice of a dose should be explained and a robust scientific justification provided. The comments given under... 

In risk characterization, step four, the human exposure situation is compared to the toxicity data from animal studies, and often a safety -margin approach is utilized. The safety margin is based on a knowledge of uncertainties and individual variation in sensitivity of animals and humans to the effects of chemical compounds. Usually one assumes that humans are more sensitive than experimental animals to the effects of chemicals. For this reason, a safety margin is often used. This margin contains two factors, differences in biotransformation within a species (human), usually 10, and differences in the sensitivity between species (e.g., rat vs. human), usually also 10. The safety factor which takes into consideration interindividual differences within the human population predominately indicates differences in biotransformation, but sensitivity to effects of chemicals is also taken into consideration (e.g., safety faaor of 4 for biotransformation and 2.5 for sensitivity 4 x 2.5 = 10). For example, if the lowest dose that does not cause any toxicity to rodents, rats, or mice, i.e., the no-ob-servable-adverse-effect level (NOAEL) is 100 mg/kg, this dose is divided by the safety factor of 100. The safe dose level for humans would be then 1 mg/kg. Occasionally, a NOAEL is not found, and one has to use the lowest-observable-adverse-effect level (LOAEL) in safety assessment. In this situation, often an additional un-... 

No-Obscncd-Advcrsc-Effcct-Levcl (NOAEL) In dose-response experiments, an exposure level at which there arc no statistically or biologically significant increases in the frequency or severity of adr erse effects between the exposed population and its appropriate control some effects may be produced at this IcN cl, but they arc not considered to be adverse, nor precursors to specific... 

After the critical study and toxic effect have been selected, the USEPA identifies the experimental exposure level representing the highest level tested at which no adverse effects (including the critical toxic effect) were demonstrated. This highest "no-obserx cd-adversc-effcct-lever (NOAEL) is the key datum obtained from the study of the dose-response relationship. A NOAEL obserx ed in an animal study in which the exposure was intermittent (such as five days per week) is adjusted to reflect continuous exposure. 

There are several limitations to tliis approach that must be acknowledged. As mentioned earlier, tlie level of concern does not increase linearly as the reference dose is approached or exceeded because the RfDs do not luive equal accuracy or precision and are not based on the same severity of effects. Moreover, luizm-d quotients are combined for substances with RfDs based on critical effects of vaiy ing toxicological significance. Also, it will often be the case that RfDs of varying levels of confidence Uiat include different uncertainty adjustments and modifying factors will be combined (c.g., extrapolation from animals to hmnans, from LOAELs to NOAELs, or from one exposure duration to anoUier). 

The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and figures may differ depending on the user s perspective. Public health officials and others concerned with appropriate actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle effects in humans or animals (LOAELs) or exposure levels below which no adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans (minimal risk levels or MRLs) may be of interest to health professionals and citizens alike. 

Cancer Effect Level-Humans A LOAEL. More Serious-Humans A LOAEL, Less Serious-Humans A NOAEL - Humans... 

Routine gross and histopathological examinations revealed no treatment-related effects on the nervous system of dogs exposed to 0.03, 0.1, or 0.3 mg/kg/day methyl parathion in the diet for 1 year (Suba 1981). In addition, there were no treatment-related effects on cholinesterase activity in plasma, red blood cells, or brains in dogs under these exposure conditions. These data are in agreement with the NOAEL established above for dogs exposed to these levels for 13 weeks. 

Cardio - cardiovascular LD = Lethal dose, 50% kill LOAEL = lowest-observable-adverse-effect level mg/kg/day = milligram per kilogram per day NOAEL = no-observable-adverse-effeot level... 

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-efifect level (NOAEL-from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs are not applicable to nonthreshold effects such as cancer. 

Tables (3-1, 3-2, and 3-3) and figures (3-1 and 3-2) are used to summarize health effects and illustrate graphically levels of exposure associated with those effects. These levels cover health effects observed at increasing dose concentrations and durations, differences in response by species, minimal risk levels (MRLs) to humans for noncancer end points, and EPA s estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction with the text. All entries in these tables and figures represent studies that provide reliable, quantitative estimates of No-Observed-Adverse-Effect Levels (NOAELs), Lowest-Observed-Adverse-Effect Levels (LOAELs), or Cancer Effect Levels (CELs).

Species The test species, whether animal or human, are identified in this column. Chapter 2, "Relevance to Public Health," covers the relevance of animal data to human toxicity and Section 3.4, "Toxicokinetics," contains any available information on comparative toxicokinetics. Although NOAELs and LOAELs are species specific, the levels are extrapolated to equivalent human doses to derive an MRL. 

NOAEL A No-Observed-Adverse-Eifect Level (NOAEL) is the highest exposure level at whieh no harmful effeets were seen in the organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system whieh was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see footnote "b"). 

CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report doses not causing measurable cancer increases. 

NOAEL In this example, 18r NOAEL is the critical end point for which an intermediate inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates to a NOAEL for the test species-rat. The key number 18 corresponds to the entry in the LSE table. The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.005 ppm (see footnote "b" in the LSE table). 

Levels of significant exposure for each route and duration are presented in tables and illustrated in figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest-observed-adverse-effect levels (LOAELs) reflect the actual doses (levels of exposure) used in the studies. LOAELS have been classified into "less serious" or "serious" effects. "Serious" effects are... 

NOAEL = no-observable-adverse-effect level Resp = respiratory wk = week(s). 

Cancer Effect Level-Animals LOAEL, More Serious-Animals LOAEL, Less Serious-Animals NOAEL - Animals... 

AP = alkaline phosphatase ATPase = adenosine triphosphatase Cardio = cardiovascular d = day(s) Endocr = endocrine F = female Gastro = gastrointestinal Gn pig = guinea pig GOT = glutamic-oxaloacetic transaminase GPT = glutamic-pyruvic transaminase Hemato = hematological hr = hour(s) LDH = lactate dehydrogenase LOAEL = lowest-observable-adverse-effect level M = male Musc/skel = musculoskeletal NOAEL = no-observable-adverse-effect level ... 

The chronic-duration oral MRL was derived based on the observation of increased serum levels of alkaline phosphatase (an indicator of hepatotoxicity) in dogs consuming 0.6 mg/kg/day for 1 year (Hoechst 1989c). The choice of this end point is supported by the observation of hydropic hepatic cells in rats that consumed 5 mg/kg/day for 2 years (EMC 1959b). The chronic-duration MRL of 0.002 mg/kg/day was derived by dividing the NOAEL for elevated serum alkaline phosphatase (0.18 mg/kg/day) by an uncertainty factor of 100 (10 for extrapolating from animals to humans, and 10 for human variability). 

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