Acute toxicity dose-response

Better fundamental understanding of material toxicity by inhalation. This will enhance our capacity to predict and model casualties. This includes the development of more Acute Exposure Guideline Levels (AEGLs), toxicity dose-response relationships for all important chemicals, and predictive toxicology. 

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. 

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 ... 

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. 

Most often, response-dose curves are developed using acute toxicity data. Chronic toxicity data are usually considerably different. Furthermore, the data are complicated by differences in group age, sex, and method of delivery. If several chemicals are involved, the toxicants might interact additively (the combined effect is the sum of the individual effects), synergisti-cally (the combined effect is more than the individual effects), potentiately (presence of one increases the effect of the other), or antagonistically (both counteract each other). 

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... 

The available data were not sufficient for the development of acute-duration inhalation or oral MRLs. Additional data are necessary to further define the dose response of phenol following inhalation, oral, and dermal exposure. Because the oral toxicity of phenol varies with the concentration of the dose, studies using varying concentrations would be useful. 

The risk assessment framework we have described for chemical toxicity is applicable to microbial risk assessment. Once the information is available on microbial hazards, which are for the most part acute (immediately observable) conditions resulting from acute (one-time) exposures, and their dose (pathogen count)-response characteristics, we should be ready to assess the risks associated with any dose of interest. Hazard information for the important pathogens is readily available but, as expected, their dose-response characteristics are much harder to come by. So with pathogen risk assessment we see the same types of uncertainties creeping into the framework as we have encountered for chemicals. 

In the first step of the hazard assessment process, aU effects observed are evaluated in terms of the type and severity (adverse or non-adverse), the dose-response relationship, and NOAEL/LOAEL (or alternatively BMD) for every single effect in aU the available studies if data are sufficient, and the relevance for humans of the effects observed in experimental animals. In this last step of the hazard assessment, all this information is assessed as a whole in order to identify the critical effect(s) and to derive a NOAEL, or LOAEL, for the critical effect(s). It is usual to derive a NOAEL on the basis of effects seen in repeated dose toxicity studies and in reproductive toxicity studies. However, for acute toxicity, irritation, and sensitization it is usually not possible to derive a NOAEL because of the design of the studies used to evaluate these effects. For each toxicological endpoint, these aspects are further addressed in Sections 4.4 through 4.10. 

The TGD (EC 2003), Chapter 3.6, addresses acute toxicity, provides guidance on data requirements, evaluation of data, and dose-response assessment for acute toxicity. 

As mentioned above, a NOAEL is usually not derived in acute toxicity smdies. It is more usual that the only numerical value derived is the LD50 or LC50 value. The LD50 or LC50 values (or the discriminating dose if the Fixed Dose Procedure was used or the result of the Acute Toxic Class Method) give an indication of the relative lethal potency of a substance. The slope of the dose-response curve is a particularly useful parameter as it indicates the extent to which reduction of exposure will reduce the lethality the steeper the slope, the greater the reduction in response for a particular finite reduction in exposure. 

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