Low dose mixture effects of endocrine disrupters and their implications for regulatory thresholds in chemical risk assessment

• Elucidation of the design principles of decisive low dose mixture experiments.
• Assessment of experimental findings that meet these design principles.
• Emphasis on observations with endocrine disrupter mixtures.
• Highlighting barriers in modern chemical risk assessment.
• Perspective on assessment of realistic exposure scenarios across the life span.

Today's chemical exposures are characterised by a widely spread blanket of contamination composed of myriads of chemicals, many of them endocrine disrupters, all at rather low levels. With their focus on considering single chemicals one by one, the approaches used by regulatory bodies worldwide for safety assessments of chemicals cannot keep up with these pollution patterns. A substantial challenge lies in the assessment of combination effects from large numbers of endocrine disrupters and other chemicals, all at low doses. We retrace the development of experimental and conceptual approaches required for assessing low dose mixtures, with an emphasis on work with endocrine disrupting chemicals. We find that nearly 20 years of research has produced good evidence for combination effects at levels around experimental thresholds. One obstacle in deciding on the relevance of this evidence is incomplete information about the range of endocrine-disrupting chemicals that make up combined exposures. These knowledge gaps need to be closed urgently, as is currently discussed under the heading of exposome research.