Review of Inhalants - ARCHIVES - National Institute on Drug Abuse

Finally, a common phenomenon with chronic intake <strong>of</strong> drugs or
toxins is the development <strong>of</strong> tolerance to the substance, so that
increased amounts <strong>of</strong> the substance are required to elicit a given
effect. It may be that the increased drug dosage which is selfadministered
consequent upon the development <strong>of</strong> tolerance for
certain drug effects may eventuate in the appearance <strong>of</strong> new toxic
signs and hence account for some <strong>of</strong> what is here termed cumulative
toxicity. Whether indeed tolerance develops to the various inhaled
solvents is still open to question. It seems almost certain that
tolerance will be observed with at least some <strong>of</strong> the solvents, and
the clinical literature on inhalant solvents is suggestive <strong>of</strong> the
development <strong>of</strong> tolerance. However, experimental data on this point
are lacking.
Dose Response Curve, Dose Effect Curves,
and Threshold Limit Values
If one has chosen some biological (in this case, behavioral) endpoint
for toxicity, for example, locomotor activity, then one can plot the
proportion <strong>of</strong> subjects who show a stipulated degree <strong>of</strong> disturbance
in this endpoint versus the dose <strong>of</strong> the volatilized drug producing
this disturbance (a dose-response curve). Alternatively, one may
quantify the degree <strong>of</strong> alteration in the endpoint, measured in
individual subjects and averaged over the group, for groups <strong>of</strong>
subjects at different doses <strong>of</strong> the drug (a dose-effect curve). This
distinction between dose-response and dose-effect functions has
been proposed by the Subcommittee on the Toxicology <strong>of</strong> Metals
under the Permanent Commission and International Association <strong>of</strong>
Occupational Health in 19’74 (Nordberg, 1976).
For most behaviors, the dose-response and dose-effect curves can
be expected to exhibit no effects when assessed at sufficiently low
concentrations and exposure durations <strong>of</strong> a toxic volatile. This
could be because <strong>of</strong> a neural “reserve” in most neurobehavioral
systems, or because <strong>of</strong> neurobehavioral abilities to compensate for a
certain degree <strong>of</strong> neural damage, or because <strong>of</strong> compensation
through neural reorganization following central nervous system
(CNS) damage. It could also be that no organic neural damage is
produced by the drug up to some dose level. At and above some
concentration-duration, however, behavioral alterations will become
apparent, and will increase in magnitude as the concentrationduration
<strong>of</strong> exposure continues to increase. The intersection <strong>of</strong> the
function <strong>of</strong> measurable behavioral effects versus drug dose with the
mean behavioral response <strong>of</strong> nonexposed (control) subjects can be
taken as a threshold limit value <strong>of</strong> the drug. This defines the
upper drug dose which is just short <strong>of</strong> producing measurable
toxicity.
Threshold Limit Values (TLV) as a term has been defined to refer
to safe levels <strong>of</strong> airborne contaminants; i.e., levels under which
“nearly all workers may be repeatedly exposed, 8 hours a day,
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