Future trends in risk analysis

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. 

PB-PK modelling allows further refinement of the dose-response evaluation by partitioning the relationship into pharmacokinetic (exposure vs. tissues dose) and pharmacodynamic (tissue dose vs. toxic response) components. This allows the uncertainties associated with each component to be assessed separately and adds accuracy to the overall animal to man extrapolation. Future developments of PB-PK modelling may allow specific sub-populations such as the newborn or individuals with metabolic variations to be taken into account. However, before this can be done there will need to be considerable growth in the amounts of physiological, pharmacokinetic and pharmacodynamic information available. 

Until very recently the risks associated with different types of chemicals such as food additives, pesticides, environmental contaminants and natural constituents of food were assessed and managed separately. However, a particular substance might fall into two or more of these categories and so the opportunity for simultaneous exposure might be overlooked. Furthermore, exposure to a chemical could occur through diet, drinking water, air pollution or dermal absorption. Aggregate exposure assessment aims to take all of the possible sources and routes of exposure into account in a realistic manner and thereby obtain a better overall estimate of risk. Initiatives have been set up in both the 

Aggregate exposure assessment is naturally more complex than the methods used for dietary risk assessment. In the simplest analysis a worst case can be established for each source and exposure route and then summed to give a total exposure. If this were below any threshold of concern such as the PTWI then no further action would be required. However, if the total worst case exposure was above a PTWI then it is unlikely to reflect the real situation since the probability that any individual would be exposed to each source by each route at the maximum level is very remote. 

When the EPA considered exposures to insecticide residues in the home they identified at least six possible sources and routes these are given in Table 2.6. Their original approach apportioned the acceptable daily intake (ADI) between the various routes but it soon became clear that this was unrealistic because an individual was unlikely to be exposed via all routes on any one day. The EPA s present strategy is to develop an approach called micro-exposure event modelling. Micro-exposure event modelling is based on statistical data on the frequencies and levels of contamination of food, water, etc. and on behavioural information about the frequency of use of lawn/pet/timber treatments, etc. The combined data are assembled in a probabilistic model called LIFELINE which is able to predict the frequency and level of exposure to a group of hypothetical individuals over their lifetime.12 The model is also able to take account of the relative proportions of different types of accommodation, the incidence of pet ownership or any other data that will affect real levels of exposure. The output from the LIFELINE model allows the exposures of individuals in a population to be modelled over any interval from a single occasion to a lifetime. 

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