STYRENE METABOLISM
& MODE OF ACTION

Mode of action refers to the way a substance acts biologically within and upon an organism. Susceptibility to a chemical’s toxic effects in different species is determined by the interaction of differences in genetic makeup, which can lead to structural, metabolic and other differences.

Understanding the underlying mechanism by which exposure to a chemical may, or may not, result in a response that produces a tumor is gaining increased importance for carcinogen risk assessment. Indeed, the U.S. Environmental Protection Agency’s (EPA’s) Draft Final Guidelines for Carcinogen Risk Assessment place much greater weight on the evaluation of mechanistic action as an interpretive tools.

Concerning styrene, state-of-the-art “lifetime” inhalation studies found lung tumors in exposed mice, but no tumors in rats, even thought the rats were exposed to much higher levels. Extensive data on workers exposed to inhaled styrene do not indicate any increase in cancer (lung or otherwise) from styrene exposure, raising a key question of why this is so.

Since mouse lung tumors became apparent, the Styrene Information and Research Center (SIRC) and its European counterpart, the Styrenics Steering Committee of Cefic, have sponsored significant research to better define the tumorogenic process (mode of action) of styrene in the mouse and examine why styrene does not seem to produce the same response in rats and humans.

It is SIRC’s position that based on this exhaustive research, undertaken over the last decade, examining styrene’s mode of action in mice versus rats versus humans that the finding of lung tumors in mice exposed to styrene is not relevant for human risk assessment.

A report published in 2002 in the peer-reviewed Journal of Regulatory Toxicology and Pharmacology summarized and interpreted the results of the SIRC/Cefic-sponsored research program. The report by George Cruzan and six co-authors is entitled “Styrene Respiratory Tract Toxicity and Mouse Lung Tumors are Mediated by CYP2F-Generated Metabolites.” Here are excerpts from the conclusions of the published paper:

“Lung tumors in mice most likely result from a nongenotoxic mode of action as a result of cytotoxicity (cell toxicity) leading to hyperplasia (non-tumorous increase in the number of cells in an organ or tissue with consequent enlargement of the affected part). No lung tumors are seen in rats exposed to styrene, where there is no evidence of cytotoxicity. No styrene-induced lung tumors would be expected in humans, which possess even less ability to metabolize styrene in lungs than rats. Indeed, no styrene-related increase in lung tumors have been reported in human cohort mortality studies…

“We conclude that styrene respiratory tract toxicity in mice and rats, including mouse lung tumors, is mediated by…metabolities. The (applicable) model predicts that humans do not generate sufficient levels of these metabolites in the terminal bronchioles to reach a toxic level. Therefore, the postulated mode of action for these effects indicates that respiratory tract effects (of styrene) in rodents are not relevant for human risk assessment.”

SIRC has provided mode of action and other relevant scientific data developed since SIRC’s inception to the EPA to inform its ongoing Integrated Risk Information System (IRIS) review of styrene.

Bookmark and Share

Styrene & Human Health Pages:

(top)