Hazard Assessment and Contaminated Sites - Dealing with Contaminated Sites: From Theory Towards Practical Application - page 528

12.3.5.2 Clinical Observations
Adverse clinical signs (gross observations) noted during the exposure period may
correlate with toxicity end points or disease processes. These can be used as
supportive evidence for dose-response relationships and may play a role in the
determination of the NOEL/NOAEL. However, not all adverse clinical signs will
correlate with pathological or morphological changes in organs or tissues. Some
will be caused by biochemical or physiological effects, i.e., incoordination, muscle
twitching, tremor, or diarrhoea may indicate acetylcholinesterase inhibition without
any morphological changes being evident in nervous tissue.
Clinical observations such as palpable tumours or those which might be associ-
ated with neoplasia (e.g., haematuria, abdominal distension, or impaired respiration)
may be useful in defining the time a tumour was first suspected as being present.
Such signs might aid in the evaluation of decreased tumour latency in long-term
rodent studies. They may also aid in determining cause of death. A statement of
the correlations, or the lack thereof, between clinical signs and specific toxicity end
points should be made in the evaluation.
The revised OECD test guidelines for 90-day oral toxicity studies in rodents
and non-rodents (Test Guidelines 408 and 409) have placed additional emphasis on
neurological end-points.
12.3.5.3 Body Weight Changes
Body weight changes (gains or losses) for individual animals and groups of ani-
mals when compared to concurrent control changes during the course of a study
are a criterion of some importance (Heywood 1981 ; Roubicek et al. 1964 ;Weil
and McCollister 1963 ). Such changes are usually related to food intake Weight
loss may not always be related to toxicity per se (Seefeld and Petersen 1984 ). The
incorporation of the test contaminant into the diet may reduce its palatability.
12.3.5.4 Haematological, Clinical Chemistry, and Urinary Measurements
Regulatory guidelines generally suggest that haematological, clinical chemistry,
and urinary parameters be routinely measured in sub-chronic and chronic toxicity
studies.
Normal biological variation in inter-animal values and their alteration in response
to a variety of inputs means that evaluators will have to contend with much “noise”
in this area, and will frequently be presented with scattered, statistically significant
effects, in the absence of any evidence of clinically significant relationships to spe-
cific toxicity end points. To deal with “noise” there is a need to examine whether
the effect noted is within the normal range of variation (concurrent and historical
controls). Note that some of these parameters can vary significantly with no clin-
ical manifestations, but others (e.g., serum potassium) have a very narrow normal
clinical range and small differences can be important.
Frequently these data show apparently “random” changes in individual group(s)
or, less commonly, non dose-related trends in changes across several groups. If using