NOAEL doses

Le systeme nerveux est le point d aboutissement principal de I action toxique des derives methyl-stanniques avec une NOAEL (dose sans effet nocif observe) d environ 0,6 mg/kg de poids corporel dans le cas des effets neuropathologiques dus aux derives dimethyles. Pour ce qui est des derives monomethyles, les donnees sont top limitees pour permettre de determiner la NOAEL. Dans le cas des derives dibutyles et mono- ou dioctyles, aucim effet neurotoxique n a etc observe. On ne dispose d aucune donnee concemant les derives monobutyles. 

There are of course many mathematically complex ways to perform a risk assessment, but first key questions about the biological data must be resolved. The most sensitive endpoint must be defined along with relevant toxicity and dose-response data. A standard risk assessment approach that is often used is the so-called divide by 10 rule . Dividing the dose by 10 applies a safety factor to ensure that even the most sensitive individuals are protected. Animal studies are typically used to establish a dose-response curve and the most sensitive endpoint. From the dose-response curve a NOAEL dose or no observed adverse effect level is derived. This is the dose at which there appears to be no adverse effects in the animal studies at a particular endpoint, which could be cancer, liver damage, or a neuro-behavioral effect. This dose is then divided by 10 if the animal data are in any way thought to be inadequate. For example, there may be a great deal of variability, or there were adverse effects at the lowest dose, or there were only tests of short-term exposure to the chemical. An additional factor of 10 is used when extrapolating from animals to humans. Last, a factor of 10 is used to account for variability in the human population or to account for sensitive individuals such as children or the elderly. The final number is the reference dose (RfD) or acceptable daily intake (ADI). This process is summarized below. 

The ADI is usually derived from a detailed analysis of the toxicology of the chemical being examined. The no observed adverse effect level (NOAEL) is determined for the most sensitive adverse effect in the test system (usually animals but occasionally humans), and a safety or uncertainty factor is applied to the NOAEL dose to derive the safe level for the general human population. 

A reference dose (RfD) estimates the lifetime dose that does not pose a significant risk to the human population. This estimate may have an uncertainty of one order of magnitude or more. The RfD is determined by dividing the no observed adverse effect level (NOAEL) dose of a substance by the product of the uncertainty and modifying factors as shown in the following equation... 

Regardless of whether ATSDR eventually adopts the studies reviewed by Tilson et al. (1990) as the basis for its MRL, the panelists suggested that the NOAEL dose from the North Carolina study should at least be cited in the toxicological profile s LSE tables. 

No adverse effect level (NOAEL) —> Dose-response relationship/curve... 

Similarly, we might be detecting an adverse effect by the test for a certain chemical or enzyme that is produced in an organ. In this instance, the sensitivity of the chemical test will be the limit of detection for the analysis. For example, perhaps 25 years ago the nature of the test using a chemical or instrumental technique could only detect a level of 10 ppm. (Below 10 ppm there is no observable color change or response from the instrument over the noise level this is the limit of detection .) Thus, if a toxicant were to produce the enzyme at 5 ppm, the old test would not detect this and the NOAEL dose would have been reached. Perhaps today, more sensitive tests would easily find the 5 ppm (or much lower) and the NOAEL would have to be re-tested. 

Each of these three factors of 10 is used to adjust the NOAEL dose reported in the mice (table 7.1). All of the factors are multiplied together to result in an overall uncertainty factor of 1,000 (10 XlO X 10). The NOAEL dose of 223 mg/kg-day is then divided by this total uncertainty factor of 1,000, resulting in a dose of 0.223 mg/kg-day. This is rounded to 0.2 mg/kg-day by the U.S. EPA. 

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). 

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. 

The LSE tables and figures do not contain NOAELs for cancer, but the text may report doses not causing measurable cancer increases. 

An increased susceptibility to Streptococcus zooepidemicus aerosol was not observed in mice exposed to 5 ppm phenol for 3 hours, or for 5 daily 3-hour periods (Aranyi et al. 1986). Neither did the phenol exposures affect pulmonary bactericidal activity towards Klebsiella pneumonia. Although tests for vulnerability to infectious agents do not represent a comprehensive evaluation of immunological competence, the 5-ppm level can be considered a NOAEL for this specific immunological effect, and is recorded in Table 2-1 and plotted in Figure 2-1. 

Intermediate-Duration Exposure. Because the human studies do not report quantitative information on dose or duration, it is not possible to know with certainty whether the combined inhalation and dermal exposures were of intermediate duration. There are intermediate-duration oral exposure data from animal studies that indicate that the liver and the hematologic systems are affected by heptachlor exposure (Enan et al. 1982 Halacka et al. 1974 Pelican 1971). The liver is probably the more sensitive of the two. No intermediate-duration oral or inhalation MRLs for heptachlor or heptachlor epoxide have been determined because of limitations in the studies, including lack of statistical comparisons, insufficient number of dose levels, no identification of NOAELs, and the description of effects that may be considered adaptive and not adverse. 

If there are several valid studies addressing the same effect from which different NOAELs could be derived, the highest reliable NOAEL not exceeding any of the reliable LOAELs should be used in the hazard assessment. If the smdies are not quite comparable, i.e., do not examine the same endpoints by equally sensitive methods, expert judgment is used to derive the most relevant NOAEL. When it is not possible to derive a NOAEL, the LOAEL should be used in the hazard assessment. 

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