Hazard and risk assessment

Another important role of the dose-response relationship is its use in the extrapolation of toxic effects seen at high doses to lower doses in order to undertake hazard and risk assessment. As already indicated for some types of toxic effect there will clearly be a dose threshold, below which there is no detectable response. This 'No Observed Effect Level' (NOEL) may apply to either a quantal response such as death or a pathological lesion

FIGURE 2.8 Comparison of the dose-response relationship for two compounds A and B. For compound A there is a response at all doses with no threshold. For compound B there is a dose or threshold below which there is a No Observed Effect Level (NOEL).

or to a response such as enzyme inhibition or binding to an endogenous receptor. The cause of the threshold may be the saturation of an enzyme or physiological repair system for example. However with some types of toxic effect such as chemical carcinogenesis for instance, the perceived mechanism supports the view that there may be no threshold for the biological effect (see also above). Thus a single molecule of carcinogen might, theoretically, be sufficient to interact with DNA and cause a permanent change in the genome of a single cell which could then lead to the development of a tumour (see Chapter 6). This one-hit type of model would give rise to a linear dose-response curve with no dose threshold when extrapolated to the point of zero response (compound A in figure 2.8). There are various

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models which have been suggested for the dose-response relationships of chemical carcinogens as well as the one-hit model, which incorporate the concept of the multistage nature of chemical carcinogenesis, the possibility of repair and the requirement for metabolic activation. The concept of a threshold dose is an important one in toxicology, particularly in terms of the extrapolation of toxic doses derived from relatively small scale animal experiments and the subsequent assessment of risk to man.

The NOEL is used in setting exposure limits such as the Acceptable Daily Intake (ADI) for chemicals such as food additives or Threshold Limit Values (TLV) for industrial chemicals, usually with a 100fold or sometimes greater safety factor to take account of species differences in response and human variability in response:

NOEL

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