Toxicology end-points

Dose-response characterisation. Different chemicals will be associated with different toxicological end-points and the risk of any individual experiencing toxicity is related to the dose that they receive. Very often it is possible to identify a dose level below which the probability of anyone experiencing an adverse effect is veiy low or zero. For additives this is usually referred to as the Acceptable Daily Intake (ADI). 

Studies of the inhalation toxicity of cresols have not been adequately detailed. The exposures involved mixtures of vapors and aerosols that were not characterized sufficiently to estimate exposure levels reliably. Furthermore, methods for evaluating the toxicological end points were not adequately described. Therefore, no LSE table or figure containing levels of significant exposure was constructed for this route. Nevertheless, certain general conclusions can be drawn from the reports regarding the toxic potential of inhaled cresols. These are discussed below. 

Aptula, A.O. and Roberts, D.W. (2006) Mechanistic applicability domains for nonanimal-based prediction of toxicological end points general principles and application to reactive toxicity. Chemical Research in Toxicology, 19, 1097-1105. 

The intermediate-duration inhalation MRL was based on a NOAEL of 0.005 ppm administered to rats for 5 hours a day, 5 days a week for 3 weeks (Mobay Corporation 1984). At 0.3 ppm, decreased kidney weights were observed in both male and female rats, with decreased liver weights observed in females only. Hepatic and renal effects were not seen at an inhaled dose of 0.15 ppm and lower. Nasal lesions occurred in 80-90% of the animals exposed at the 0.3 ppm level, while only 50-70% of the animals were affected at the 0.15 ppm concentration. No significant lower respiratory tract alterations were noted at the 0.0175 ppm inhalation dose (NOAEL) however, at the same 0.0175 ppm dose, hemorrhage, inflammatory exudate, epithelial changes were observed in the nasal cavity. The 0.0175 ppm dose is also classified as an extra-thoracic respiratory tract LOAEL and is the toxicological end point that this intermediate-duration MRL is based upon. For the purposes of MRL derivation, the minimal LOAEL was placed at 0.0175 ppm and the NOAEL was placed at 0.005 ppm. Since there is no reported threshold for HDI immrmological hypersensitivity in hmnans, this MRL may not be protective for persons with hypersensitivities to HDI. Respiratory tract lesions in laboratory animals have been described in other studies (Dow Chemical 1964 E.l. Dupont de Nemours 1978 Haskell Laboratory 1961 Karol et al. 

The particular cell line used in our laboratory, AHH-1 TK-(-/- cells (Crespi and Thilly, 1984), is a versatile indicator cell line for a variety of in vitro toxicological end points (Crespi et al., 1993 Crofton-Sleigh et al.,... 

In some instances additional specialized studies may be required to assess drug-specific toxicological concerns. For example, hypersensitivity tests may be required for the -lactam antibiotics FDA has recently been concerned with how this standard human food safety assessment process accurately determines the safe concentration of antibiotic residues based on the traditional toxicological end-points. Of particular concern was the impact of low levels of antibiotics on the intestinal microflora. 

Sijm, D. T. H. M., M. Schipper, and A. Opperhuizen, Toxicokinetics of halogenated benzenes in fish Lethal body burden as toxicological end point , Environ. Tox. Chem., 12,1117-1127 (1993). 

Dose-response characterisation. Different chemicals will be associated with different toxicological end-points and the risk of any individual experiencing toxicity is related to the dose that they receive. Very often it is... 

Non-thresholded chemicals that are not carcinogens are less frequently identified. For many years lead was considered to be thresholded because its effects on haemoglobin synthesis were not seen at low doses. However, recent work into the effects of lead on mental development suggest that there may be no threshold for this end-point. Food is a relatively minor source of lead exposure compared with air and dust in urban environments. For chemicals that relate to toxicological end-points that do not show thresholds it is not possible to identify a NOAEL or PTWI. In such cases it is desirable to estimate the level of risk associated with a given level of exposure. 

A vital and often over-looked aspect of risk evaluation is ensuring that the estimate of intake corresponds to the PTWI so that like is being compared with like. For example, toxicological end-points are frequently time-related. On rare... 

The extent of the database on health effects in animals resulting from exposure to organotin compounds is clearly shown in Figure 2-5. Except for genotoxic studies, there are oral studies that describe all the other toxicological end points considered in this profile. By contrast, the information is more limited for the inhalation and dermal routes of exposure. 

Despite the numerous tissue- and species-specific responses that have been observed and the elegant work on the molecular mechanisms mediating some of these, there exists a considerable gap between knowledge of these changes and the degree to which they are related to the biological and toxicological end points elicited by 2,3,7,8-TCDD and related compounds. These chemicals have been shown to alter... 

Dose-response curves for various toxicological end points for a given congener must run parallel. 

The dose-response curves for a given toxicological end point must run parallel for the various congeners. 

In general the safety evaluation of the finished product can be obtained by ascertaining the toxicity profile of the different ingredients. But it is important to evaluate each different toxicological end point and if the documentation is adequate for the assessment. 

Cronin, M.T.D. and Dearden, J.C., QSAR in toxicology. 4. Prediction of non-lethal mammalian toxicological end points, and expert systems for toxicity prediction, Quant. Struct.-Act. Relat., 14, 518-523, 1995b. 

It should be emphasized that these methods will generally be considered for an acute lethal endpoint. Their use to set AEGL-1 and AEGL-2 values will be considered on a chemical-by-chemical basis. Different endpoints may require the use of different data sets in different or the same species, a different benchmark dose approach, or identification of a different response level. These factors wiU be considered for specific chemicals and toxicologic end-points. 

Additional research regarding the health effects of acute-duration inhalation exposure to uranium would be useful these studies should include toxicological end points, lung doses, and metabolic fate. 

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