Hypothesis-driven weight of evidence evaluation indicates styrene lacks endocrine disruption potential.

Styrene is among the U.S. EPA's List 2 chemicals for Tier 1 endocrine screening subject to the agency's two-tiered Endocrine Disruptor Screening Program (EDSP). Both U.S. EPA and OECD guidelines require a Weight of Evidence (WoE) to evaluate a chemical's potential for disrupting the endocrine system. Styrene was evaluated for its potential to disrupt estrogen, androgen, thyroid, and steroidogenic (EATS) pathways using a rigorous WoE methodology that included problem formulation, systematic literature search and selection, data quality evaluation, relevance weighting of endpoint data, and application of specific interpretive criteria. Sufficient data were available to assess the endocrine disruptive potential of styrene based on endpoints that would respond to EATS modes of action in some Tier 1-type and many Tier 2-type reproductive, developmental, and repeat dose toxicity studies. Responses to styrene were inconsistent with patterns of responses expected for chemicals and hormones known to operate via EATS MoAs, and thus, styrene cannot be deemed an endocrine disruptor, a potential endocrine disruptor, or to exhibit endocrine disruptive properties. Because Tier 1 EDSP screening results would trigger Tier 2 studies, like those evaluated here, subjecting styrene to further endocrine screening would produce no additional useful information and would be unjustified from animal welfare perspectives.