Dose level choosing

If the test substance contains only 75% active ingredient and the investigator chooses a constant dose volume of 10 ml kg 1 body weight across all dose levels, it will be more convenient to prepare a stock solution such that when 10 ml kg 1 of this stock solution is given to the animal, the dose will be the desired one (say 500 mg kg 1 of active ingredient). The concentration of this stock solution would be (500mg/10ml)/0.75 = 66.7mg of the test substance per milliliter of diluent. 

Most chemicals do not cause toxic or adverse effects until a certain dose has been given. These are called threshold chemicals. The lowest dose level at which there are no adverse effects observed in the test animals is called the No Observed Adverse Effect Level (NOAEL) and is the starting point for the calculation of the reference dose. While the terminology used may differ among regulatory agencies, the concepts are similar. In North America, the term margin of safety or exposure is used, whereas in Europe an Acceptable Operator Exposure Level (AOEL) is used. Care is taken to choose the NOAEL for an effect which is relevant to humans and that the duration, frequency and route of exposure in the test animals are relevant to the human exposure. 

The EMTD is determined on the basis of a subchronic toxicity study in which small groups of test animals are exposed to a fairly broad dose range of the test substance for a period of approximately 10% of the life span of the animals (90 days for rodents). In turn, the dose levels which are tested in the 90 day subchronic study are themselves based on information generated in acute toxicity studies of the type described in the preceeding chapter. In addition to providing the EMTD the acute and subchronic tests also are utilized to obtain information on the metabolism of the test substance, the extent to which the test substance and its metabolites are distributed and bioaccumulated in the host, and which host organ systems may be affected by exposure. This information may be of importance in choosing the species or strains to be used in the chronic study as well as the route of administration. 

The first treated animal was a female which received 75 mg/kg of quinine hydrochloride by slow manual intravenous injection over 2 minutes. Although this injection was performed slowly, no perflisor was used and it lasted only two minutes. This injection period was too short. Consequently, after injection, the dog was agitated. Thereafter, it had convulsions and died 22 minutes after the injection. Due to these marked clinical signs followed by death, no ophthalmological examinations were performed after injection and it was decided to increase the injection period and to choose dose levels up to 75 mg/kg. 

Exposure Assessment. What is the dose or the level of exposure of humans to the chemical agent This question must be asked in the context of a given policy for controlling the uses and dissemination into the environment of a chemical agent. This control policy might be the present situation, a possible new regulatory policy, or a policy that a chemical manufacturer or distributor could choose to impose on his product. It Is usually appropriate to assess the exposure of specific groups of people, Which may depend on occupation, life style, purchases and uses of certain products, etc. 

A related issue is the patient s ability to metabolize and eliminate drugs adequately. For example, lithium is excreted entirely by the kidneys, and if a patient suffers from significantly impaired renal function, high, potentially toxic levels could develop on standard doses. Although the dose could be adjusted to compensate for the decrease in drug clearance, it might be more appropriate to choose another mood stabilizer such as valproate or carbamazepine, because they are primarily metabolized through the liver. 

To understand how blood levels relate to efficacy or toxicity in order to choose efficacious and safe doses... 

In a designed experiment, whether a variable is a fixed or random effect depends on whether a researcher has control over that variable. A fixed effect is one where the researcher can choose the level(s) of the variable to represent the precise contrast of interest. For example, the doses of drug used in a study or the time points that... 

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