Dose-Response Analysis
Dose response analysis is a step where we establish what would be a safe dose from assessments of dose versus health outcomes. This differs between cancer health effects and non-cancer health effects. In case of cancers, there is no upper theoretical level, and dose responses are usually read off from either animal studies or epidemiological studies assuming a linear statistical model. For non-cancer health effects, we usually identify a threshold level at which the lowest possible health effects or least possible health effects at or above the expected frequencies. Such levels are referred to as no observed adverse exposure level or low observed adverse exposure levels. In exposure assessment, we measure the amount of the environmental toxin to which a person is exposed.After we have completed the hazard identification process, we will next conduct two steps in parallel. One of the two steps is to conduct a dose-response analysis. Depending on the nature of the health outcome, we will have different approaches to conducting the dose-response analysis. If I am studying a non-cancer health effect, then my dose-response assessment will be something like a safety assessment where I will identify if there is a "safe" level of exposure or dose for which there is no additional worse effect, or very low levels of adverse health effects. On the other hand, if my health outcome is a cancer, then it is no more a matter of "acceptable" risk. At all levels of exposure, we should strive to bring down the risk of cancer as we do not know at what molecular level the induction of tumour takes place. Hence, a "threshold" model will not work for us.
Difference between exposure and dose
We need to distinguish between exposure and dose. We know that we are exposed to the toxicants in the environment through various pathways. We can inhale a toxin (such as a toxic gas), or we can ingest a toxin in two ways - we can drink a toxin dissolved in a liquid (such as tea or another beverage), or water (dissolved in water as microbes and chemicals such as arsenic); we can also be exposed by eating (toxins that are dissolved or in the form of food; food poisoning bacteria, or heavy metals, or children often put soil in their mouth, or pica, for example). Once the toxin enters the body, then it does something to the body (toxicokinetics) and the body does something to it (toxicodynamics). The toxin can reach liver carried by the blood stream where it is metabolised. After metabolism in the liver, the metabolites are carried by the blood-stream to the kidneys where they are excreted through urine. Exposure refers to the concentration of toxin in the environment and dose refers to the amount or concentration of the toxin at the site in the body where it is going to act in the form in which it is going to act. For example, inorgnanic arsenic dissolved in drinking water is associated with cancer and non-cancer effects; inorganic arsenic exposure is associated with bladder cancer \cite{Tsuji:2014cz}. But it is not inorganic arsenic that is associated with such effects, they are caused arsenic metabolite, notably MMA3 \cite{Melak:2014hl}.
For those exposures that are not associated with cancers (non-carcinogens), EHRA is essentially a safety assessment. Here, the aim of the EHRA process is to identify the lowest level of exposure that will result in an acceptable level of health risk. In order to do this, for the exposure (chemicals or other agents), the level of exposure at which health effects manifest are studied. Some health effects are significant and serious; others are non-serious. Some health effects manifest at very low levels of exposure: these health effects are sensitive health effects. Some of the health effects are very sensitive; the most sensitive health effect such as skin lesions may or may not be serious. On the other hand, there may be serious health effects such as cardiovascular effects that are manifest at doses higher than that lead to the manifestation of the highly sensitive yet trivial or non-serious health effects. These effects can be critical health effects. The critical health effects are identified from the hazard identification steps and then these significant or critical health effects are studied with respect to the dosage in which they manifest.
The lowest dose at which the critical yet non-cancers health effects that manifest and the ones that are not beyond their baseline risks is referred to as no observed adverse effects level (NOAEL). For some combinations of exposure and disease conditions, a NOAEL is not possible. There are other situations, where the health effects are manifest but these manifest at certain levels of exposure. These are referred to as lowest observed adverse effect level (LOAEL). The NOAEL and LOAEL are threshold levels. Thus, for non-cancerous health effects, the focus is on finding the apparent safe levels of exposure rather than finding out conducting a risk assessment. With cancerous health effects, the aim is to eliminate risks at all levels. In risk assessments that involve cancerous health effects, the dose response graph is studied and the specific levels of the dosage in which the effects are manifested are charted. As many dose response charts are studied in the contexts of animal studies where very high doses are involved, these doses are unsustainable or impractical in human beings. As a result, most dose-response studies in humans for carcinogens are studied using extrapolation from large dose studies to low or ultra low dose studies. The goal of these extrapolation exercises is to see what would be the result in terms of health effects if the dosage is at the level of human scale (this is in the form of mg or micrograms/Kg of body weight or for inhalation agents, on a scale of mg or weight per L of air).
Because of this, dose response curves for cancerous health effects are studied assuming that there is a linear dose response function between the exposure or dose and the health effect (see Figure 2 to view a linear dose response association).