Toxicology of Industrial Compounds

volumes, masses and blood flows of different organs, partition coefficients
of 1,3-butadiene between blood and organs/tissues and for metabolic
capacities in liver and lung (bronchial and alveolar areas), accurate dosedependent
simulations were performed for the uptake of 1,3-butadiene in
mice and rats in gas-closed chambers. Moreover, with the resulting model
the relative importance of lung metabolism as compared to metabolism in
the liver was predicted for the three different species. Lung metabolism
appeared to be much more important than liver metabolism in mice, this in
contrast to the situation in the rat and humans. Moreover, at low exposure
concentrations the relative importance of lung metabolism was predicted to
increase in mice as a result of diminished saturation of metabolism in this
species. It was concluded that the observed species differences in lung vs
liver metabolism of 1,3-butadiene (mice>rat>human) and the tendency
towards increased lung metabolism at low doses might rationalize the
observed species differences in the lung carcinogenicity of 1,3-butadiene
and this knowledge should be useful in the in vivo extrapolation from high
dose to low dose risk assessments within one species as well as in
interspecies risk assessment extrapolations.
Conclusions
In conclusion, a profound knowledge of the biodisposition and the
toxicokinetics of a toxic or potentially toxic chemical is of utmost
importance to the design and interpretation of laboratory assessments of
toxicity, to explain interspecies differences in toxicities and to extrapolate
more reliably from animal experiments to man in the process of risk
assessment. This also holds true for the design for proper biological
monitoring procedures and for the interpretation of the results in terms of
potential health risks of exposure to chemicals. Apart from traditional
compartment-based toxicokinetic approaches, more recent physiologicallybased
toxicokinetics modeling approaches have distinct advantages for the
above-mentioned purposes.
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