Dose calculation case study

EUSES. As in the case of USEtox model, the present model provides outputs such as human intake fraction of a certain substance for different exposure pathways. In the present case study, estimation of the human intake doses for Guiyu was calculated. These results were compared with the incidence and severity of the effects (dose-response assessment). 

Case study of 14-year-old boy who died after ingesting 1.5 g potassium dichromate [0.53 mg chromium(VI)]. Since body weight was not reported, the standard 70 kg body weight was used to calculate the dose of 7.5 mg chromium(Vl)/kg. n>... 

Once the phase 1 has been completed, next steps include the comparison of observed human exposure data (maximum concentration, Cmax and area under the concentration-time curve, AUC) to the exposures observed in the supportive preclinical studies, prediction of the human exposure in future clinical trials (based on dose level and frequency) and the calculation of the actual safety margins provided by the repeat-dose preclinical toxicology studies. The need for safety margins (based on preclinical safety and single-dose human data) to support phase lb or phase 2 dosing is usually considered on a case-by-case basis. 

The toxicological characterizations (EDio, BMD, TEF and TED), the calculation of the doses from exposures, and the risk characterization (Total MOE) are illustrated in the case study that follows. 

In most cases studied in low viscous solutions and in organized media of low viscosity, kt c was found much higher than the corresponding k, and k r [27-29]. Therefore, in a good approximation, kj is dose to the trans-cis photoisomerization rate constant. The radiative rate constant k may be calculated from experimental values of Tfl and Ofl according to the following equation ... 

In the case of noncarcinogenic substances, there exists a threshold this is an exposure with a dose below which there would not be adverse effect on the population that is exposed. This is the reference dose (RfD), and it is defined as the daily exposure of a human population without appreciable effects during a lifetime. The RfD value is calculated by dividing the no observed effect level (NOEL) by uncertainty factors. When NOEL is unknown, the lowest observed effect level (LOEL) is used. NOEL and LOEL are usually obtained in animal studies. The main uncertainty factor, usually tenfold, used to calculate the RfD are the following the variations in interspecies (from animal test to human), presence of sensitive individuals (child and old people), extrapolation from subchronic to chronic, and the use of LOEL instead of NOEL. Noncancer risk is assessed through the comparison of the dose exposed calculated in the exposure assessment and the RfD. The quotient between both, called in some studies as hazard quotient, is commonly calculated (Eq. 2). According to this equation, population with quotient >1 will be at risk to develop some specific effect related to the contaminant of concern. 

An average fatal dose of 1.52 mg/kg cyanide for humans has been calculated from case report studies of intentional or accidental poisonings (EPA 1987a). The lowest fatal oral dose reported in humans is 0.56 mg/kg cyanide (Gettler and Baine 1938). 

Baldessarini and Davis (1980) attempted to clarify whether there is a significant relationship between the antipsychotic maintenance dosages administered and the risk of relapse in the case of chronic schizophrenics. Correlations calculated for 23 controlled studies showed no relationship between the administered doses of antipsychotics and the risk of relapse within a wide range. Based on this result, the authors ruled that the maintenance dosage for each individual patient should be kept as low as possible in order to prevent antipsychotics from causing undesirable delayed effects. 

In many cases, because of the uncertainty about the subsequent product, companies often choose to use the worst-case following product, which would be the product having the smallest batch size and the largest daily dose for calculation purposes. In that case, the limit would be valid no matter what product is subsequently introduced in the manufacturing sequence and the company could go ahead and finish its cleaning validation study. 

In the effects assessment step the relationship between the level of exposure and the incidence, nature, and severity of an (adverse) effect following the exposure is determined. For most types of effects, it is assumed that there is a minimum dose or concentration below which adverse effects will not occur the no effect level or threshold. To determine the threshold, different doses are tested, for most chemical hazards usually in laboratory animals. In toxicology, the highest tested dose without adverse effects is called the no observed adverse effect level (NOAEL). Based on the NOAEL established in an experimental study, a human limit value can be calculated, taking into account uncertainties and differences in experimental design and circumstances. Uncertainties and differences are accounted for by uncertainty factors (e.g., for interspecies differences, intraspecies variability, and exposure duration). For some types of substances, it is assumed that every level of exposure can result in adverse effects, in which case no threshold would exist. This, for instance, is assumed to apply for genotoxic carcinogens. 

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