A critical review finds styrene lacks direct endocrine disruptor activity

Abstract

The European Commission lists styrene (S) as an endocrine disruptor based primarily on reports of increased prolactin (PRL) levels in S-exposed workers. The US Environmental Protection Agency included S in its list of chemicals to be tested for endocrine activity. Therefore, the database of S for potential endocrine activity is assessed. In vitro and in vivo screening studies, as well as non-guideline and guideline investigations in experimental animals indicate that S is not associated with (anti)estrogenic, (anti)androgenic, or thyroid-modulating activity or with an endocrine activity that may be relevant for the environment. Studies in exposed workers have suggested elevated PRL levels that have been further examined in a series of human and animal investigations. While there is only one definitively known physiological function of PRL, namely stimulation of milk production, many normal stress situations may lead to elevations without any chemical exposure. Animal studies on various aspects of dopamine (DA), the PRL-regulating neurotransmitter, in the central nervous system did not give mechanistic explanations on how S may affect PRL levels. Overall, a neuroendocrine disruption of PRL regulation cannot be deduced from a large experimental database. The effects in workers could not consistently be reproduced in experimental animals and the findings in humans represented acute reversible effects clearly below clinical and pathological levels. Therefore, unspecific acute workplace-related stress is proposed as an alternative mode of action for elevated PRL levels in workers.

Keywords:

• lists of endocrine disruptors in EU and US
• screening studies
• animal studies
• epidemiology
• (anti)estrogenicity
• (anti)androgenicity
• thyroid hormone activity
• prolactin
• stress
• neurotransmitters
• dopamine

Acknowledgement

The authors gratefully acknowledge the very useful comments offered by 6 anonymous reviewers who were selected by the Editor. These review comments were very helpful in strengthening the manuscript and clarifying key points.

Declaration of interest

The preparation of the manuscript was financially supported by the Styrenics Steering Committee (SSC) in PlasticsEurope and by the Styrene Producers Association (SPA) in CEFIC. SSC and SPA are Sector Groups in the aforementioned industry associations. The members of these Sector Groups are major styrene producing and using companies in Europe. HPG is a private consultant working for the SSC and received funding by SSC. MB is employed by Lyondell Chemical Company, a company that manufactures and uses styrene. EL is employed by BASF SE, a company that manufactures and uses styrene. MP is a private consultant working for Styrolution, a company that manufactures and uses styrene. SLS is a faculty member at Baylor College of Medicine and has no interest to declare. HPG served as an observer for industry when the classification of styrene was discussed by the RAC of ECHA in Europe. Prior to 2012 EL, MB and HPG had several contacts with European national authorities regarding classification for carcinogenicity and reproductive toxicity of styrene. Apart from this, none of the authors has appeared before regulatory agencies or in litigations related to styrene. The authors have the sole responsibility for the writing and content of the paper and the interpretation and views expressed in the paper are not necessarily those of the authors’ employers.

Supplementary material available online

Supplementary Appendix to be found online at http://informahealthcare.com/doi/abs/10.3109/10408444.2015.1064091