INDEX initial toxicity

In the Mond Index the plant is divided into individual units on the basis of the feasibility of creating separating barriers. One of the factors taken into account in the index is therefore plant layout. The potential hazard is expressed in terms of the initial value of a set of indices for fire, explosion and toxicity. A hazard factor review is then carried out to see if design changes reduce the hazard, and intermediate values of the indices are determined. Offsetting factors for preventative and protective features are applied and the final values of the indices, or offset indices, are calculated. The elements of the Mond method are listed in Table 1. 

Chemical Exposure Index (CEI) (Chemical Exposure Index, 1994 Mannan, 2005, pp. 8/22-8/26.) The CEI provides a method of rating the relative potential of acute health hazard to people from possible chemical release incidents. It may be used for prioritizing initial process hazard analysis and establishing the degree of further analysis needed. The CEI also may be used as part of the site review process. The system provides a method of ranking one risk relative to another. It is not intended to define a particular containment system as safe or unsafe, but provides a way of comparing toxic hazards. It deals with acute, not chronic, releases. Flammability and explosion hazards are not included in this index. To develop a CEI, information needs include... 

Toxicity studies should be designed not only to identify a safe dose, but also a toxic dose(s) to anticipate the product s safety and to better define the therapeutic index in humans. Specific product considerations that may complicate the process of defining a toxic dose may include limits based on formulation, lack of significant systemic absorption, or the amount of the product available. The lack of significant toxicity in animals does not necessarily mean that the product is safe. The margin of safety for the initial starting dose, however, will likely be adequate. 

Toxicology studies are conducted to define the safety profile of a candidate and include definition of the no-toxic-effect dose, MTD, potential organs of toxicity, and potential biochemical markers to detect and track toxic events. Most developmental compounds that do not become therapeutic products have unacceptable toxicity in animals or humans. Before the definitive toxicology studies needed to support an IND submission are initiated, a number of animal experiments can be conducted to characterize the potential toxicity of the candidate. These early toxicology evaluations are usually conducted in the same species as used in pharmacology evaluations. As mentioned earlier, the lowest dose that has no toxicity or an acceptable level of toxicity is compared with the dose that gives the desired pharmacologic response in the same animal species to obtain a therapeutic ratio or index for that species. 

AMPHETAMINES BUPROPION 1. t plasma concentrations of these substrates, with risk of toxic effects 2. t risk of seizures. This risk is marked in elderly people, patients with a history of seizures, those with an addiction to opiates/ cocaine/stimulants, and those with diabetes treated with oral hypoglycaemics or insulin 1. Bupropion and its metabolite hydroxybupropion inhibit CYP2D6 2. Bupropion is associated with a dose-related risk of seizures. These drugs that lower seizure threshold are individually epileptogenic. They have additive effects when combined 1. Initiate therapy with these drugs, particularly those with a narrow therapeutic index, at the lowest effective dose. Interaction is likely to be important with substrates for which CYP2D6 is considered the only metabolic pathway (e.g. amphetamines) 2. Extreme caution. The dose of bupropion should not exceed 450 mg/day (or 150 mg/day in those with severe hepatic cirrhosis)... 

CINACALCET BUPROPION T plasma concentrations of these substrates, with risk of toxic effects Bupropion and its metabolite hydroxybupropion inhibit CYP2D6 Initiate therapy of these drugs, particularly those with a narrow therapeutic index, at the lowest effective dose. Interaction is likely to be important with substrates for which CYP2D6 is considered the only metabolic pathway (e.g. hydrocodone, oxycodone, desipramine, paroxetine, chlorpheniramine, mesoridazine, alprenolol, amphetamines, atomoxetine)... 

Managing pediatric victims of chemical terrorism is an especially difficult challenge. In addition to the obvious physiologic and anatomic differences compared to adults (Table 61.1), there are important psychological and behavioral differences that put children at risk (Rotenberg and Newmark, 2003). Anecdotal reports have claimed that children are likely to be the first to manifest symptoms, to develop more severe manifestations, and to be hospitalized for other related illnesses. In fact, it is anticipated that children will be overrepresented among the initial index cases in a mass civilian exposure to toxic chemicals. Children have many characteristics that make them vulnerable to toxic exposures. The smaller mass of a child automatically reduces the dose of toxic agents needed to cause... 

Basic Mechanisms. Finally, further work is necessary on fundamental mechanisms of individual fire retardants. These mechanisms are a function of the particular chemicals involved and the environmental conditions of the fire exposure. There is a need to establish common methods and conditions for determining these mechanisms in order to compare different treatments. This would give us a better understanding of how these compounds work in action and would provide a more efficient approach for formulating fire-retardant systems than a trial and error approach. Correlations also need to be established between rapid precise thermal analysis methods and standard combustion tests. Retardant formulations could be evaluated initially on smaller (research and development size) samples. The more promising treatments could be tested for flame-spread index, heat release rate, and toxic smoke production. 

A variety of parameters are included into the QSAR equation. Log P is a commonly used parameter and is obtained from Medchem or estimated using the CLOGP3 computer program. Molecular weight is calculated. In interspecies models the LD50 or LC50 value is incorporated as a typical parameter. Molecular connectivity indexes, electronic charge distributions, and kappa environmental descriptors have been proven as powerful predictors of toxicity. The efficacy of these values lies in the fact that each of these parameters describes a molecule in a fashion similar to that actually seen by the molecular receptors that initiate a toxic response. Substructural keys are identified with the help of the MOLSTAC substructural key system. MOLSTAC consists of five classes of descriptors ... 

The HI Approach For historical reasons seemingly based on data availability, the HI approach is the most often used approach, and it is traditionally applied to noncarcinogens. The hazard index is found by integratings the exposure level and the related toxicity into a single value with potency-weighted dose additions. The HI approach is simple to implement but somewhat limited in its scope, however, since it can underpredict or overpredict risk estimates. Initially... 

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