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Biochemic and hematologicdeterminations are made and all animals necropsied. Thus thepurpose of such studies are extended and allot of information isobtained including i) Dosage for further studies (i.e. subacuteand chronic testing), ii) Therapeutic index can be calculatedfor drugs, and most important iii) Clinical effects such as bodysystem and organ effects can be determined so that subsequentstudies can more specifically exam these effects more closely. Acute toxicity studies may therefore be considered as a startingpoint to determine “toxicity” but must consider animal welfareconcerns.
Page 2-40Subchronic Toxicity: This category refers primarily to resultsobtained following thirty to ninety days of exposure. Although, occasionally fourteen-day exposures are used. There is not general agreement as to call these other timedstudies subchronic, prolonged, three month, ninety day, sixweeks or whatever. Probably the best and most accurate is toreference the toxicity data by the number of days of exposure. A usual design would involve rats at three different dosagelevels; the highest is 25% of the LD50and the lowest is at a notoxic level, and one group half way between these dosages; afourth non-exposed control group must always be included. Ifrodents are used then thirty to forty animals equally divided bysex are used per group (remember males and femalesmetabolize chemicals differently). If dogs or large animals areused then six to ten animals are used per group, againrepresenting equal numbers of males and females. Thecompound is usually administered in the feed or drinkingwater to avoid daily handling and stress.Biochemical (serum enzymes, electrolytes, proteins and fats)and hematologic (Blood cells) determinations are made atintervals and all animals are necropsied. At necropsy, allorgans and tissues are examined for pathology (abnormalities). More detailed blood, serum and pathology tests may berequired if acute testing demonstrated specific effects. Otherdata collected includes weekly body weights, feed and waterconsumption and clinical signs. More detailed clinicalexamination of specific systems may be required (i.e. nervoussystem) if acute testing showed specific effects. Another use ofsubchronic tests is for range finding to determine dosages forchronic studies.Chronic Toxicity: Chronic toxicity studies are conducted todetermine the effects of continuous long-term exposure. Astudy lasting more than ninety days is referred to as a chronicstudy. In rodent, chronic toxicity studies the toxicant exposureis 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 isusually twenty-four months unless there are overridingconcerns. Some studies may last seven to ten years in thesespecies. A chronic toxicity protocol will often include at leastone rodent and one non-rodent species.Usually three dose levels plus controls are used. The dosagesused are usually below that which causes overt clinical illness.