Chemistry Reference
In-Depth Information
increase of response is observed as the dose gets larger.
This describes “saturable” phenomena at higher doses,
typical of many chemicals that require bioactivation by
metabolism. Whether we assume that a dose-response
has a threshold or follows a linear relationship at a low
dose usually follows from our understanding of mecha-
nism of toxicity. For example, low-dose linear responses
are assumed when a chemical is found to be muta-
genic. Instances of a “threshold” effect at a low dose are
assumed whenever a chemical depletes the body's natu-
ral capacity to fi ght toxicity, perhaps by the inactivation
of critical proteins as the chemical dose increases.
100
75
50
25
1.3 Defi nitions of Dose and Response
Determination of the dose-response relationship,
which is the association between dose and the inci-
dence of a defi ned biological effect in an exposed pop-
ulation usually expressed as percentage (Nordberg
et al, 2004), depends on the numerical evaluation of
both dose and response. Dose is defi ned as the total
quantity of a substance administered to, taken up,
or absorbed by an organism, organ, or tissue (Nor-
dberg
et al.
, 2004) and can be measured with
in vitro
or
in vivo
experiments. When measured
in vivo
, doses
are usually expressed as milligrams per kilogram of
body weight in the case of oral exposure, as parts per
million or billion (ppm/ppb
*
) in cases of inhalation
exposure, or milligrams per square meter in cases of
dermal exposures.
In vitro
dosing units will depend
on the experiment that is usually described as concen-
trations (e.g., ppm or
0
0
1
2
3
4
Effect (E)
FIGURE 4
Point-to-point plots for the relationships between
effect and percent response at equi-dose levels based on data from
Figure 1, using dose levels of D = 1, 2, 3, and 4.
The interrelationship among dose, effect, and
response has been presented as a three-dimensional
model by Loewe (1959) and Hatch (1968). Although
three-dimensional models are conceptually useful, the
data necessary to construct them are not usually avail-
able, and such models are not considered further here.
Quantitatively, the generated relationship can then
be used, after the application of several uncertainty
factors, in estimating risk guidance values to humans
when exposed to the same chemical. For example,
the animal-derived dose-response relationship can be
used to estimate the dose level at which no signifi cant
increase in response over background occurs. This dose
level is referred to as the “No Observed Adverse Effect
Level” (NOAEL) that is fundamental in the applica-
tion of risk assessment to hazardous chemicals. Dose-
response modeling in occupational epidemiology is
usually motivated by questions of causal inference
(e.g., Is there a monotonic increase of risk with increas-
ing exposure?) or risk assessment (e.g., How much
excess risk exists at any given level of exposure?).
Qualitatively, the shape of the dose-response curve
can be indicative of underlying mechanisms. Usually,
the shape of the curve varies along the dose ranges
applied. In some instances, no response is observed
until a dose large enough is applied to elicit a signifi -
cant response. This dose is referred to as a “threshold.”
In other cases, there may be a gradual increase in the
response as the dose increases. This increase may fol-
low a linear or curvilinear relationship at a low dose.
The magnitude of this increase may shrink as the dose
range is elevated. At high enough doses, a further
g/L) in the medium where the
experiment is conducted.
Effect can be defi ned as a graduated biological
change in a continuum of changes that can be quan-
titatively measured. For biological effect to be use-
ful in dose-response relationships it has to be readily
quantifi able. It is common for a chemical to cause mul-
tiple effects, some effects occurring simultaneously
in time, and some effects interacting with each other.
The measured effect in the dose-response relationship
has to also be independent from other exposures. This
assumption of independence is important because it
ensures the direct relationship between the dose and
the measured response. If response depends on other
responses caused by the chemical, it will be diffi cult to
associate the response with the delivered dose.
The measured effect can quantitatively fall within
one of the following:
µ
*
The SI unit for concentration of a substance in air is mg/m
3
,
which is ppm multiplied by molecular weight in grams divided by
24.45 (at 25°C and 1 atmosphere).
