Dose-response relationships
See the following Videos:
https://www.youtube.com/watch?v=UqCEADtuIgc
https://www.youtube.com/watch?v=THr7roac0cA
Every day we are exposed to a variety
of chemicals present in the food, in the air, personal care products,
etc. However, there are a number of factors that will influence the
outcome of a chemical exposure and whether or not a toxic effect will
occur: dose, chemical structure, route of exposure, etc.
Considering the route of exposure, different target organs may be involved in the toxic response. Also, chemical structure gives information about the possible interactions and toxic effects on the exposed organisms and how it is both metabolized and excreted.
As in the video example, the dose or amount of a chemical to which an individual is exposed has a great influence on toxicity. Generally, lower chemical dose (or exposure) levels have no toxic effects. However, increasing chemical dose levels increases the possibility of the occurrence and severity of toxic response. This can be expressed graphically in the form of a dose-response curve and this is a major concept in toxicology and the basis for all toxicity tests (Figure 1).
Figure 1 - Dose-response curve and LD50 value.
Source: Robinson L and Thorn I. (2005)
Dose can be defined as the total amount
of a chemical that is administered to a living organism. Taking into
account the toxicokinetics and toxicodynamics of the administered
chemical, the total amount of the chemical in a specific body
compartment is referred as concentration. Hence, in whole animal
experiments, we usually talk of doses that produce a given magnitude of
adverse effect.
The OECD guidelines define dose-response as "the relationship between dose and the proportion of a population sample showing a defined effect". Theoretically, whatever response is selected for measurement, a classic sigmoid-shaped curve is obtained, although in practice this is not often seen.
It is important to recognize that a given chemical can have multiple target sites or mechanisms of toxicity resulting in different molecular, biochemical and cellular effects, each with its own "dose-response" relationship. Thus, in the case of population-level "dose-response" characterization, the observed response is an integration of multiple individual "dose-response relationships".
There are some exceptions to this
hypothesis, namely endocrine disrupting chemicals, which can also
induce adverse effects at low dose levels, frequently different to the
effects reported at higher doses (Figure 2). In fact, endocrine disrupting chemicals can have a non-monotonic
responses with a U or an inverted U shape response-curve.
Figure 2 - Non-conventional dose-response relationship involving low-dose effects and compensation.
Source: Hodgson E. (2010)
These non-conventional dose-response
relationships have been observed with respect to both acute and chronic
toxicity and are particularly relevant to the risk assessment process,
typically established attending levels of exposure that were
anticipated to pose no harm. These low-level effects may potentially
have interest in homeopathic approaches to treating diseases, based
upon the premise that exposure to some chemicals at subthreshold
levels, as defined by standard acute toxicity evaluations, can elicit
toxicological and pharmacological effects.
In figure 2 (I) is described a response to chemical exposure followed by a compensatory response that returns the normal response of the organism. In figure 2 (II) occurs a negative response due to overcompensation (hormesis). Hormesis can be defined as an overcompensatory response to some disruption in homeostasis resulting in a U or inverted U-shaped deflection at the low end of the dose-response curve. Finally, as represented in figure 2 (III), the compensatory ability is overcome at high dose levels of the chemical, above which the standard dose-response curve occurs. For some endocrine disrupting chemicals, no dose-response curve is observed.
The magnitude of chemical response is dependent on the chemical concentration at the receptor, which in turn depends on the administered dose and chemical properties (absorption rate, distribution, metabolism ...).
The potency is a measure of the chemical amount needed to induce a specific response. The lower the dose required to induce a certain effect, the more potent is the chemical. Potency is frequently expressed as the effective concentration (or dose) of a chemical that induce a 50% of a known maximal response (EC50 or ED50). A chemical with a lower EC value is more potent that others with higher EC values. Hence, as shown in figure 3, chemical A has the lowest EC50 value, being the most potent chemical.
Figure 3 - Dose-response relationships for four chemicals (A, B, C and D) that have the same efficacy but differ in terms of their potency.
Source: http://tmedweb.tulane.edu/pharmwiki/doku.php/drug_receptor_theory
Similarly, it is important to define
the impact of chemical exposure on the whole population. These studies
typically involve a certain range of doses and measure an all-or-none
response (such as the presence of tail abnormalities in the embryo). In
this case, the dose that induces that specific effect in 50% of the
population is referred to as the "median effective dose" but is also
abbreviated EC50 or ED50.
The efficacy is the maximal response induced by chemical exposure and depends on the number of chemical-receptor complexes and the efficiency of an activated receptor to induce an effect. The affinity is the chemical ability to interact with its receptor. Considering EC50 as the effective concentration that induces 50% of a known maximal response, each chemical (A, B, C and D) in figure 4 has essentially the same EC50 value (equi-potent) but they differ in terms of maximum response they can produce at high concentrations when all available receptor sites are saturated. Chemical A shows the highest efficacy between the four compounds, with a relative efficacy that is nearly 100 times more than chemical D.
Figure 4 - Dose-response relationships for four chemicals (A, B, C and D) with different efficacy.
Source: http://tmedweb.tulane.edu/pharmwiki/doku.php/drug_receptor_theory
