Hazard Assessment and Contaminated Sites - Dealing with Contaminated Sites: From Theory Towards Practical Application - page 524

• cause a body weight decrement from concurrent control values of greater than

10-12%;

• in a dietary study, exceed 5% of the total diet because of potential nutritional

imbalances caused at higher levels;

• produce severe toxic, pharmacological or physiological effects that might shorten

duration of the study or otherwise compromise the study results;

• in a carcinogenicity study, alter survival in a significant manner due to effects

other than tumour production.

High doses which overwhelm normal mechanisms for metabolism, detoxification
and/or excretion, or produce severe tissue damage (i.e., necrosis, demyelination) can
make interpretation difficult or lead to inappropriate conclusions about the extent of
the hazard.
It is commonly accepted that the lowest dose should not produce any evidence of
toxicity (i.e., allows the establishment of an NOAEL).

Dosing Route

For repeat-dose studies, the most convenient route of administration is by dietary
admixture. However, depending on the possible route of exposure of the public or
occupationally exposed workers to a contaminant or an environmental contaminant,
it may need to be investigated by the dermal and/or inhalational route.
For dermal exposure the material, in a suitable vehicle, is applied to the clipped
skin of rats, rabbits or guinea-pigs; OECD test guideline No. 410 recommend even
application to an area representing about 10% of the total body surface area using
methods that avoid dislodgement or evaporation.
The surface area of the respiratory tract is approximately 50-100 m 2 in the nor-
mal adult and much more air (about 5000 times, by volume) is inhaled each day
than food or water is ingested (McClellan and Henderson 1989 ). Thus, exposure to
airborne material is potentially greater than via dermal or oral exposure. Airborne
material can be gases or vapours, liquid droplets or solutions, aerosols (solid and
vapour components), or dry fibres or powders. As a consequence, the mechanisms
needed to deliver contaminants to a test chamber in a form that can be inhaled
are quite complex, particularly when coupled with the need to include measuring
devices which can establish particle size, concentration and form of the material
in the exposure chamber. Furthermore, many factors can influence the inhalation,
deposition and retention of inhaled materials in the respiratory tract. Therefore, the
conduct of inhalational studies is considerably more complex than equivalent stud-
ies by the dietary or dermal routes. Of critical importance, in both the conduct and
assessment of such studies, in the need to establish what portion of the material
delivered to the exposure chamber was in a respirable form.

Study Findings - Physiological, Pharmacological, or Toxic?

Responses produced by contaminants in humans and experimental animals may
differ according to the quantity of the contaminant received and the duration and