Octamethylcyclotetrasiloxane (D4) lacks endocrine disruptive potential via estrogen pathways

Octamethylcyclotetrasiloxane (D4) is a volatile, highly lipophilic monomer used to produce silicone polymers found in many consumer products and used widely in industrial applications and processes. Many reviews of the toxicology of D4 conclude that its adverse effects on endocrine-sensitive endpoints occur by a MoA dependent on systemic toxicity rather than one mediated via endocrine activity, but others identify D4 as an estrogenic endocrine disruptive chemical (EDC) based on results of screening-level assays indicating that D4 interacts with ERα and at high doses, affects estrogen-sensitive endpoints in rodents. To resolve these divergent interpretations, we tested two specific hypotheses related to the interaction of D4 with estrogen receptor-alpha subtype (ERα) at the biochemical and molecular levels of biological organization and a third specific hypothesis related to estrogenic and anti-estrogenic pathways at the physiological level. At the physiological level, we used an established WoE methodology to evaluate all data relevant to estrogen agonist and antagonist activity of D4 by examining its effects on ERα-relevant endpoints in rodent toxicology studies. At the biochemical level, we calculated whether D4 could produce a functionally significant change in the ERα occupancy by 17β-estradiol (E2) using equations well-established in pharmacology. For these calculations, we used data on the potency and kinetics of D4 from studies in rats as well as published potency and affinity data on endogenous estrogens and their circulating concentrations in humans. At the molecular level, we used established molecular docking techniques to evaluate the potential for D4 and related chemicals to fit within and to activate or block the binding pocket of ERα. Our analyses indicate that the estrogenic effect of D4 is molecularly, biochemically, and physiologically implausible, which corroborates previous evaluations of D4 that concluded it is not an estrogenic endocrine disruptor. The claim that D4 exhibits estrogenic endocrine disruptive properties based on a presumed link between the results of screening-level assays (RUA and ERTA) and adverse effects is not supported by the data and relies on deficient evaluative and interpretative methods. Instead, a plausible mechanistic explanation for the various adverse effects of D4 observed in rodent studies, including its effects in reproduction studies, is that these are secondary to high-dose-dependent, physico-chemical effects that perturb cell membrane function and produce rodent-specific sensory irritation.