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1000
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Abstract/Summary
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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has evaluated whether MAK values which are derived from systemic effects in inhalation experiments in animals or in volunteers at rest should reflect that the respiratory volume at the workplace, and therefore the amount taken up, is higher than under these experimental conditions. Assuming that the same external concentration in the air leads to the same internal exposure in all species at rest, it is taken into account when extrapolating data from inhalation studies in animals to humans that in the case of systemic effects the body burden (related to kg body weight) of the worker at the workplace, with an assumed respiratory volume of 10 m3 in 8 hours, is about twice as high as that of the experimental animal in the usual 6‐hour experiment. The equivalent external concentration at the workplace is, therefore, half of that used in the experiment. This extrapolation applies only for gases and vapours with a blood:air distribution coefficient of > 5 and for aerosols, provided that the effect is the product of cd7;t. If it can be shown that the critical effect depends more on the concentration than the product of cd7;t and that the steady state was reached within the duration of the experiment, the equivalent concentration at the workplace is two thirds of the concentration used in the experiment, as then extrapolation of the usual 6‐hour exposure in animal experiments to the 8‐hour exposure at the workplace is no longer necessary. When deriving MAK values for systemic effects from studies with volunteers at rest, the MAK value is established at half of the concentration used in the volunteer study, which is calculated from the ratio of the respiratory volume of workers to that of persons at rest. Gases and vapours with a blood:air distribution coefficient of < 5 represent an exception. In addition, the results are extrapolated to the longer daily exposure at the workplace, unless there are toxicokinetic data available that show this to be unnecessary. If there are valid PBPK models of exposure with the relevant metabolites in humans and animals, these are used for extrapolation from the experimental animal to persons at the workplace.
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