How to Differentiate General Toxicity-Related Endocrine Effects from Endocrine Disruption: Systematic Review of Carbon Disulfide Data

Abstract

This review provides an overview of the assessment of the endocrine disrupting (ED) properties of carbon disulfide (CS₂), following the methodology used at the European level to identify endocrine disruptors. Relevant in vitro, in vivo studies and human data are analyzed. The assessment presented here focuses on one endocrine activity, i.e., thyroid disruption, and two main adverse effects, neurotoxicity and cardiotoxicity. The data available on the different ED or non-ED modes of action (MoA), known to trigger these adverse effects, are described and the strength of evidence of the different MoA is weighted. We conclude that the adverse effects could be due to systemic toxicity rather than endocrine-mediated toxicity. This assessment illustrates the scientific and regulatory challenges in differentiating a specific endocrine disruption from an indirect endocrine effect resulting from a non-ED mediated systemic toxicity. This issue of evaluating the ED properties of highly toxic and reactive substances has been insufficiently developed by European guidance so far and needs to be further addressed. Finally, this example also raises questions about the capacity of the technics available in toxicology to address such a complex issue with certainty.

Keywords: carbon disulfide; cardiotoxicity; endocrine disruptors; neurotoxicity; thyroid disruption.

Figure 1

Information flow diagram.

Figure 2

Simplified overview of the experimental design of the EOGRTS: TH measurements [44]. PND: postnatal day; LD: lactating day, M: males; F: females.

Figure 3

Postulated MoA for CS₂: decreased TH levels and subsequent adverse atherosclerosis, adapted from Duntas et al. (2018).