TR 052 : Styrene Toxicology Investigations on the Potential for Carcinogenicity | August 1992
At present there is no clear evidence that styrene is carcinogenic in laboratory animals or in man. The absence of an exposure related oncogenic response in several animal bioassays or appropriate epidemiology investigations precludes the use of quantitative risk assessment procedures. Concern has been expressed, however, that a putative carcinogenic potential exists as a result of the formation and presence in tissues of styrene 7,8-oxide, an intermediate metabolite of styrene.
To address these concerns new toxicokinetic data on styrene and the metabolic occurrence of styrene oxide have been generated and are presented together with information on macromolecular binding in vivo. The toxicokinetic parameters for styrene and styrene oxide permit a quantitative description of the major pathways of styrene and styrene oxide in the rat and mouse under various conditions of exposure.
Based on experimental data a physiologically based pharmacokinetic (PB-PK) model for styrene and styrene oxide has been developed, validated and used to calculate the body burden of styrene and styrene oxide for man in relation to animals in terms of AUCSO (AUCSO is the area under the concentration time curve for styrene oxide in blood). This approach referred to as “semiquantitative margin of safety” (“SMS”) provides the opportunity to assess the putative hazard of styrene to man in relation to specific conditions in laboratory animals. Comparison of predicted and measured AUCSO values in animals with that in man exposed to an anticipated workplace concentration of 50ppm styrene shows AUCSO values up to 400 times lower in man than in exposed animals in which no treatment related oncogenic response was observed.
In addition, the results of DNA binding studies showed that styrene metabolism in the rat or the mouse does not lead to the production of biologically significant DNA binding intermediates. Studies with styrene oxide failed to find any evidence of DNA binding while investigation with styrene showed only minute levels of binding considered too low to cause an increase in the incidence of cancer.
It can be concluded that the carcinogenic potential of styrene, if one exists at all, must be so low that occupational or environmental exposure to styrene is unlikely to present any genotoxic or carcinogenic hazard for man.