Biochemic and hematologic determinations are made and all animals necropsied

Biochemic and hematologic determinations are made and

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Biochemic and hematologic determinations are made and all animals necropsied. Thus the purpose of such studies are extended and allot of information is obtained including i) Dosage for further studies (i.e. subacute and chronic testing), ii) Therapeutic index can be calculated for drugs, and most important iii) Clinical effects such as body system and organ effects can be determined so that subsequent studies can more specifically exam these effects more closely. Acute toxicity studies may therefore be considered as a starting point to determine “toxicity” but must consider animal welfare concerns.
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Page 2-40 Subchronic Toxicity: This category refers primarily to results obtained following thirty to ninety days of exposure. Although, occasionally fourteen-day exposures are used. There is not general agreement as to call these other timed studies subchronic, prolonged, three month, ninety day, six weeks or whatever. Probably the best and most accurate is to reference the toxicity data by the number of days of exposure. A usual design would involve rats at three different dosage levels; the highest is 25% of the LD 50 and the lowest is at a no toxic level, and one group half way between these dosages; a fourth non-exposed control group must always be included. If rodents are used then thirty to forty animals equally divided by sex are used per group (remember males and females metabolize chemicals differently). If dogs or large animals are used then six to ten animals are used per group, again representing equal numbers of males and females. The compound is usually administered in the feed or drinking water to avoid daily handling and stress. Biochemical (serum enzymes, electrolytes, proteins and fats) and hematologic (Blood cells) determinations are made at intervals and all animals are necropsied. At necropsy, all organs and tissues are examined for pathology (abnormalities). More detailed blood, serum and pathology tests may be required if acute testing demonstrated specific effects. Other data collected includes weekly body weights, feed and water consumption and clinical signs. More detailed clinical examination of specific systems may be required (i.e. nervous system) if acute testing showed specific effects. Another use of subchronic tests is for range finding to determine dosages for chronic studies. Chronic Toxicity: Chronic toxicity studies are conducted to determine the effects of continuous long-term exposure. A study lasting more than ninety days is referred to as a chronic study. In rodent, chronic toxicity studies the toxicant exposure is the greater portion of the expected life span of the species, often eighteen months in mice and twenty-four months in rats. If dogs or primates are used then the duration of exposure is usually twenty-four months unless there are overriding concerns. Some studies may last seven to ten years in these species. A chronic toxicity protocol will often include at least one rodent and one non-rodent species. Usually three dose levels plus controls are used. The dosages used are usually below that which causes overt clinical illness.
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