No adverse effect level

Safety factor An uncertainty factor that is used in combination with the no-adverse-effect level data to estimate the safe human dose. 

Data for humans show that adverse effects occur at concentrations in air >1.0 mg PCP/m3 and in tissues at more than 8 mg/kg fresh weight (Table 23.7). No adverse effects were noted at daily intakes of 2.1 mg per 70-kg adult or 30 pg/kg BW, up to 1.01 mg/L in drinking water, <0.5 mg/m3 in air, <0.5 mg/L in blood plasma, and <1.0 mg/L in blood (Table 23.7). It is noteworthy that the recommended PCP air concentration of 0.5 mg/m3 results in a daily intake of 2.5 to 3.8 mg (based on 15 to 23 m3 of air inhaled daily, 8-h exposure), equivalent to 42 to 63 pg/kg BW for a 60-kg female. These levels are higher than the currently recommended no-adverse-effect level of 30 pg/kg BW daily (Table 23.7), and overlap or exceed the 58 to 74 pg/kg BW daily range — a level recommended by Williams (1982). Air concentrations >1.0 mg PCP/m3 can produce respiratory irritation in unacclimatized individuals, but concentrations as high as 2.4 mg/m3 can be tolerated by conditioned individuals (USEPA 1980). The biological tolerance value of <1000 pg PCP/L in blood, recommended by Ziemsen etal. (1987), is based on occupational air exposure studies exposure to maximum average air concentrations of 0.18 mg PCP/m3 for up to 34 years produced blood PCP residues of 23 to 775 pg/L, with no measurable adverse effects. The authors concluded... 

No-adverse-effect levels Food, upper safe limit, 70-kg adult Wood, in contact with food Drinking water Recommended Global proposed Upper safe limit Arizona California Kansas, Montana Maine New York... 

LABORATORY WHITE RAT Diet No adverse effect level Lowest adverse effect level (histological damage) 4.0 mg/kg ration, equivalent to 0.29-0.38 mg toxaphene/kg body weight daily (Chu etal. 1988) 20.0 mg/kg ration (Chu etal. 1988)... 

The U.S. FDA has issued a guidance document that assists both the toxicologist and the clinician to propose the first dose in man.12 The starting dose becomes a fraction (often 10%) of the lowest no-adverse-effect level (NOAEL) in the rodent or nonrodent repeated dose studies. This is an oversimplistic statement and the reader is referred to the specifics of the guidance. 

LOAEL), and the highest dose at which no effects are observed, the no adverse effect level (NOAEL). In the interest of prudence, the NOAEL is generally considered as a conservative estimate of the toxicity threshold. 

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). 

The approach recommended by the ECETOC (1995) is to derive the best scientific estimate of a Human No-Adverse-Effect Level, referred to in the report as the Predicted No-Adverse-Effect Level (PNAEL). The approach distinguishes three stages ... 

Derivation of approximations of the distribution of assessment factors from historical data (based on NOAEL ratios) has limitations as the use of the NOAEL instead of the True No-Adverse-Effect Level brings along the variation (error) in the NOAELs. 

For oral to inhalation route-to-route extrapolation (28 substances), the Predicted Inhalation No-Adverse-Effect Level (NAEL) was often higher than the observed NOAEL (for inhalation) implicating that the substance was considered less toxic after extrapolation when compared with the experimental observations. Based on the 95th percentile of the lognormal distribution of the ratios between the predicted NAEL and the observed NOAEL, UFs ranging from 75 to 201 for the different extrapolation methodologies were found. 

The 4-hour LCso in rats was 3200 ppm. Rats exposed for 6 hours/day for 7 days to 1500 ppm had mild tremor, slight incoordination, and slight irritation of eyes and extremities. A no-adverse-effect level for 65 days, 6 hours/ day, 5 days/week, was 5 90 ppm in rats. 

An important outcome of the JECFA evaluation is the establishment of an ADI for a food additive. The ADI is based on the available toxicological data and the no adverse effect level in the relevant species. JECFA defines the ADI as an estimate of the amount of a food additive, expressed on a body weight basis, that can be ingested daily over a lifetime without appreciable health risk (8). JECFA utilizes animal data to determine the ADI based on the highest no-observed-adverse-effect level (NOAEL), and a safety factor is applied to the NOAEL to provide a margin of safety when extrapolating animal data to humans. JECFA typically uses safety factors of 50, 100, or 200 in the determination of an ADI. The NOAEL is divided by the safety factor to calculate the ADI. The food additive is considered safe for its intended use if the human exposure does not exceed the ADI on a chronic basis. This type of information may potentially be used to help assess the safety of a pharmaceutical excipient that is also used as a food additive, based on a comparison of the ADI to the estimated daily intake of the excipient. 

First, we recognize that every substance has a toxicity level. Any substance will produce some adverse effect at a high enough test level. Evaluating safety requires that this potential adverse effect be Identified and that adequate toxicological data are available to determine the level at which exposure to the substance can be considered safe. This is done by determining a "no-adverse-effect" level in... 

Third, safety factors are based on a "no-adverse-effect" level. Testing In more than one animal species provides a better reflection of what to expect In the human, and allows extrapolation of safety data from the animal to the human by the use of a safety factor. In determining an ADI for humans, the FDA applies a safety factor to the highest "no-adverse-eflfect" level determined in an appropriate animal study. The safety factor Is Intended to account for differences between the animal and human and to provide an adequate margin of safety for the consumer. 

To substantiate the safety of the substance for the population exposed, a subchronic study must be performed. The study should be designed to obtain a no-adverse-effect level. A 90- or 28-day study in rats is usually used. 

EU, European Union NOAEL, no adverse effect level, the highest level of intake at which no adverse effects are observed. 

The U.S. /Canadian report (Instimte of Medicine, 1997) quotes a no adverse effect level of 60 /rg per day, leading to a tolerable upper level of intake of 50 /xg per day (and 25 /xg per day for infants). The toxic threshold for adults has not been established, but reports of hypercalcemia in adults have involved intakes in excess of 1,000 /xg per day. There is no evidence of adverse effects at plasma concentrations of calcidiol lower than 140 nmol per L, which requires an intake in excess of 250 /xg per day, suggesting that the currently accepted no adverse effect level is lower than necessary (Vieth, 1999). 

The effects on IQ have been questioned and some smdies have not replicated these effects. The most recent publication (R. L. Canfield et al, InteUecmal impairment in children with blood lead concentrations below to pg per dedliter, New England Journal of Medicine, 348 (2003), 1517-26) suggested effects occurring at levels below 100 pg/litre and reported a correlation between blood lead levels and IQ. They found a decrease in IQ as blood lead increased from 10 to too pg/litre. However, measurement of IQ is not precise and has many potential confounding factors. In rats the no adverse effect level (NOAEL) is 50 pg/Htre. 

A concentration of 0.4-0.5 ppm for up to 8 h is generally eonsidered a no-adverse-effect level for nose and eye irritation (Anglen, 1981 Rotman et al, 1983 D Alessandro et al., 1996). Nasal airway resistanee and pulmonary peak flow are not affected at 0.5 ppm (Shusterman et al, 1998 Schins et al, 2000). At 1 ppm, some subjects report slight nose, throat, and eye irritation, and transient alterations in pulmonary funetion tests may occur. A concentration of 4 ppm was eonsidered a nuisance level of nose and throat irritation (Joosting and Verberk, 1974). 

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