Dose-response characterisation

For many substances the body s own mechanisms for de-toxification and repair mean that low doses of some chemicals can be tolerated without experiencing any adverse effects. However, once a certain threshold has been exceeded then the degree of adverse effect is related to the dose. The highest dose at which no adverse effects are observed in the most susceptible animal species is identified as the No Observed Adverse Effect Level (NOAEL). The NOAEL is used as the basis for setting human safety standards for food additive Acceptable Daily Intakes (ADIs)4 

The ADI was defined by the Joint WHO/FAO Expert Committee on Food Additives and Contaminants (JECFA)5 as  

UF2 = uncertainty factor to allow for inter-individual variability in humans. 

Uncertainty factors usually have a default value of 100 so that the ADI is usually equal to the NOAEL x 100. If human data are available then UFi is usually taken to be one. Note that the NOAEL and ADI are corrected for bodyweight. 

This is to allow for the fact that smaller individuals (e.g. children) can tolerate relatively lower doses before ary adverse effect is experienced. 

The PTWI is defined as the amount that an individual can ingest weekly over a lifetime without appreciable health risk. It is related to the NOEAL so that  

Where UFi = Uncertainty factor to allow for extrapolation from animal species to humans. 

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Dose-response characterisation. Different chemicals will be associated with different toxicological end-points and the risk of any individual experiencing toxicity is related to the dose that they receive. Very often it is possible to identify a dose level below which the probability of anyone experiencing an adverse effect is veiy low or zero. For additives this is usually referred to as the Acceptable Daily Intake (ADI). 

Dose-response characterisation. Different chemicals will be associated with different toxicological end-points and the risk of any individual experiencing toxicity is related to the dose that they receive. Very often it is... 

In recent years it has become increasingly apparent that for chemical contaminants that are abundant in the environment a more sophisticated approach to dose-response characterisation is required. There is increasing evidence that small but significant sub-populations are exposed to intakes that exceed PTWIs and most people are exposed to potential carcinogens through their diet. In such cases the PTWI concept is redundant because it is necessary to assess the actual levels of risk to which individuals are exposed in order to introduce proportionate control measures. Simply knowing that the hazard exists is not sufficient. 

Metabolomics studies the entire metabolism of an organism. It is possible to consider characterising the complex pattern of cellular proteins and metabolites that are excreted in urine. Pattern recognition techniques of nuclear magnetic resonance spectra have been applied to determine the dose-response using certain classical liver and kidney toxicants (Robertson et al, 2000). This could well provide a signature of the functional state of the kidney, and perturbations in the pattern as a result of exposure to a chemical could be observed. But first it would be necessary to understand how compounds with known effects on the kidney affect these processes. 

In section 2.3 of this chapter the present approach to characterisation of dose-response relationships was described. In most cases it is necessary to extrapolate from animal species that are used in testing to humans. It may also be necessary to extrapolate from experimental conditions to real human exposures. At the present time default assumptions (which are assumed to be conservative) are applied to convert experimental data into predictive human risk assessments. However, the rates at which a particular substance is adsorbed, distributed, metabolised and excreted can vary considerably between animal species and this can introduce considerable uncertainties into the risk assessment process. The aim of PB-PK models is to quantify these differences as far as possible and so to be able to make more reliable extrapolations. 

In the concept proposed in 1983 in the US, risk assessment comprised of four steps, namely, hazard identification, dose-response analysis, exposure analysis, and risk characterisation. In a simplified procedure of risk assessment, only three types of information is needed, namely, physico-chemical characteristics, toxicology, the behavior of the chemical at the use situation. The physicochemical data is supposed to show some sense of toxicity and behaviour of the chemical. The toxicology data shows the kind of symptoms to be elucidated, the target organism, and the amount of chemicals needed for showing the symptoms. Behaviour data would show the extent the receptor - here, humans or other natural organisms - is contacted by the chemical at the use situation. The risk assessment is simply to compare the extent the receptor is contacted and the amount of the chemicals needed to show the symptom. 

Ideally, a health risk assessment would characterise the dose-response relationship, i.e. the relationship between the dose of a chemical administered or received and the incidence and/or severity of an adverse health effect in an exposed population. However, estimating the dose-response relationship for many chemicals (particularly environmental agents) is often extremely difficult or, because of the lack of data, unachievable. For example, little is known about dermal uptake rates of soil-bound contaminants or the duration of such contact episodes. Therefore, estimating the dose received from dermal contact with soil can be highly tentative and is usually based upon a number of simplifying assumptions. 

After hazard identification, hazard characterisation is undertaken, and this is normally based on dose-response relationships in the range of toxicological studies summarized in Section 2.5.1. It is assumed that a threshold dose for response can be identified, where the NOEL is the highest dose that causes no (adverse) detectable effect in the most sensitive animal species or strain. Other approaches have been used, however, such as determination of a benchmark... 

The dose response relationship between seven commonly used herbicides and four luminescence-based bacterial biosensors was characterised. As herbicide concentration increased the light emitted by the test organism declined in a concentration dependent manner. These dose responses were used to compare the predicted vs. observed response of a biosensor in the presence of multiple contaminants. For the majority of herbicide interactions, the relationship was not additive but primarily antagonistic and sometimes synergistic. These biosensors provide a sensitive test and are able to screen a large volume and wide range of samples with relative rapidity and ease of interpretation. In this study biosensor technology has been successfully applied to interpret the interactive effects of herbicides in freshwater environments [12]. 

Risk characterisation integrates data from hazard identification, dose-response and exposure assessments to describe the overall risk from a pesticide. It develops a qualitative or quantitative estimate of the likelihood that any of the hazards associated with the pesticide will occur in exposed people. It also involves the assumptions used in assessing exposure as well as the uncertainties that are built into the dose-response assessment [3]. 

Risk assessment is a multidisciplinary task related to toxicology, analytical chemistry, biochemistry, molecular biology, health disciplines, politics, etc. The four key aspects of risk assessment are hazard identification, dose response, exposure assessment and risk characterisation. They are all driven by dynamics based on intake, absorption and effect. 

ECHA (2010) Chapter R.8 Characterisation of dose (concentration)-response for hiunan health. Guidance on information requirements and chemical safety assessment. ECHA-2010-G-19-EN... 

Verain and coworkers (3) described the formulation of an effervescent paracetamol tablet dosed at 500 mg, containing saccharose and sorbitol as diluents. Other components were anhydrous citric acid, sodium or potassium bicarbonate, PVP, and sodium benzoate. The tablets were characterised by measurement of a number of responses, in particular the friability, the volume of carbon dioxide produced per tablet when it is put in water, and the time over which the tablet effervesced. The objective was to study the effects of 4 factors, the quantities of sorbitol and of citric acid per tablet, the nature of the bicarbonate (whether sodium or potassium bicarbonate), and the effect of different tableting forces on these responses. The... 

One of the other benefits is that CO is already produced in the body naturally. So providing that the CO dose is controlled carefully there are unlikely to be too many side effects due to the CO itself. Although great care needs to be taken in assessing the behaviour of the fragments that are left behind after CO release. Currently, there is not much detail in the literature about the characterisation of the fragments left behind after CO-release even if they have shown that it is non-toxic and not responsible for the beneficial effects observed. 

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