Dose-response relationship, toxic

Dose-Response Evaluation The process of quantitatively evaluating toxicity information and cliaracterizing the relationship between the dose a contaminant administered or received, and the incidence of adverse health effects in the exposed population. From a quantitative dose-response relationship, toxicity values can be derived that are used in the risk characterization step to estimate the likelihood of adverse effects occurring in humans at different exposure levels. 

The task for ecotoxicity assessment is to provide qualitative and quantitative indicators of the potential environmental impacts of chemicals, such as changes in the abundance of individual species or the diversity of the species community, taking into account the concentration and the time of exposure (dose-response relationships). Toxic action at the level of the organism may be classified according to Ariens (1984) ... 

If possible, there should be measurement of the toxic effect in order quantitatively to relate the observations made to the degree of exposure (exposure dose). Ideally, there is a need to determine quantitatively the toxic response to several differing exposure doses, in order to determine the relationship, if any, between exposure dose and the nature and magnitude of any effect. Such dose—response relationship studies are of considerable value in determining whether an effect is causally related to the exposure material, in assessing the possible practical (in-use) relevance of the exposure conditions, and to allow the most reasonable estimates of hazard. 

In addition to the effect of biological variabihty in group response for a given exposure dose, the magnitude of the dose for any given individual also determines the severity of the toxic injury. In general, the considerations for dose—response relationship with respect to both the proportion of a population responding and the severity of the response are similar for local and systemic effects. However, if metabohc activation is a factor in toxicity, then a saturation level may be reached. 

Although acute lethal toxicity has been used as an example, the principles discussed apply ia general to other forms of toxicity capable of being quantitated ia terms of dose—response relationships. 

Acute Toxicity Studies. These studies should provide the following information the nature of any local or systemic adverse effects occurring as a consequence of a single exposure to the test material an indication of the exposure conditions producing the adverse effects, in particular, information on dose—response relationships, including minimum and no-effects exposure levels and data of use in the design of short-term repeated exposure studies. 

Reproductive Toxicity. No data are available that impHcate either hexavalent or trivalent chromium compounds as reproductive toxins, unless exposure is by way of injection. The observed teratogenic effects of sodium dichromate(VI), chromic acid, and chromium (HI) chloride, adininistered by injection, as measured by dose-response relationships are close to the amount that would be lethal to the embryo, a common trait of many compounds (111). Reported teratogenic studies on hamsters (117,118), the mouse (119—121), and rabbits (122) have shown increased incidence of cleft palate, no effect, and testicular degeneration, respectively. Although the exposures for these experiments were provided by injections, in the final study (122) oral, inhalation, and dermal routes were also tried, and no testicular degeneration was found by these paths. 

There are some basic differences between toxic and allergic reactions. The most important differences are (1) an allergic reaction always requires a prior exposure to the compound, and this reaction only occurs in sensitized individuals and (2) a dose-response relationship is characteristic to a toxic reaction, whereas such a relationship is much less clear for an allergic reaction. Even minute doses can elicit an allergic reaction in a sensitized individual (see Fig. 5.42). ... 

Scientific information for the process of establishing OELs may come from human or animal data obtained using different methods, from studies of acute, subacute, and chronic toxicity through various routes of entry. Human data, which is usually the best source, is not easily available, and frequently it is incomplete or inadequate due to poor characterization of exposure and clear dose-response relationships. Human data falls into one of the following categories ... 

Dose-response relationship 1 he toxicological concept that the toxicity of a substance depends not only on its toxic properties, but also on the amount of exposure or dose. 

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. 

No dose-response relationship can be established for the developmental toxicity of methyl parathion from the available database. All reliable LOAEL values in rats for developmental effects for the acute- and intermediate-duration categories are recorded in Table 3-3 and plotted in Figure 3-2. 

Dose-Response Relationship—The quantitative relationship between the amount of exposure to a toxicant and the incidence of the adverse effects. 

Bolla-Wilson K, Bleecker ML, Agnew J. 1988. Lead toxicity and cognitive functioning A dose response relationship. 16th Annual International Neuropsychological Society Meeting, January 27-30, 1988. J Clin Exp Neuropsychol 10 88. 

AEGL-1 (Non-disabling) NRa NR NR NR Not recommended due to steep dose-response relationship, mechanism of toxicity, and because toxicity occurs at or below the odor threshold... 

Uncertainty Factors/Rationale Total uncertainty factor 30 Interspecies 10—The 10-min LC50 value for the monkey was about 60% of the rat value and one-third the rabbit value. The mouse data were used to calculate the AEGL levels, because the data exhibited a good exposure-response relationship and the endpoint of decreased hematocrit levels can be considered a sensitive indicator of arsine toxicity. In addition, arsine has an extremely steep dose-response relationship, allowing little margin in exposure between no effects and lethality. 

Toxicity endpoint AEGL-2 values were based upon a 3-fold reduction in the AEGL-3 values. This estimate of a threshold for irreversible effects was justified because of the absence of exposure-response data related to irreversible or other serious, long-lasting effects and the steep dose-response relationship indicated by the data that was available on monomethylhydrazine... 

Grimm C, Schmidli H, Bakker F et al (2001) Use of standard toxicity tests with Typhlodromus pyri and Aphidius rhopalosiphi to establish a dose response relationship. J Pest Sci 74 72-84... 

Effect of Dose and Duration of Exposure on Toxicity. No studies were located where -hexane concentration was measured in workplace air before workers became ill, so no dose-response relationship can be defined for human neurotoxicity as the result of -hexane exposure. Information on duration of exposure leading to toxicity is available from some case series reports. An occupational exposure caused sensory disturbances in the lower extremities after approximately 2 months (Herskowitz et al. 1971). A case of peripheral neuropathy after 7 months of exposure was reported among press-proofing workers in Taipei (Wang et al. 1986) a serious case resulting in quadriplegia after 8 months of exposure was reported among sandal workers in Japan (Yamamura 1969). Based on case reports, it can be estimated... 

The duration of repeat-dose studies should be at least as long as the proposed clinical study. These studies are designed to establish a dose-response relationship, define target organ(s) of toxicity, and determine whether observed toxicities are reversible. Evaluation parameters should include not only those routinely performed in the acute studies, but those performed in the additional studies as well. Special tests, such as ophthalmoscopic, electrocardiograph, body temperature, and blood... 

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