Biochemic and hematologic determinations are made and

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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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.