Applying the adverse outcome pathway concept for assessing non-monotonic dose responses: biphasic effect of bis(2-ethylhexyl) phthalate (DEHP) on testosterone levels

Male reproduction is one of the primary health endpoints identified in rodent studies for some phthalates, such as DEHP (Bis(2-ethylhexyl) phthalate), DBP (Dibutyl phthalate), and BBP (Benzyl butyl phthalate). The reduction in testosterone level was used as an intermediate key event for grouping some phthalates and to establish a reference point for risk assessment. Phthalates, and specifically DEHP, are one of the chemicals for which the greatest number of non-monotonic dose responses (NMDRs) are observed. These NMDRs cover different endpoints and situations, often including testosterone levels. The presence of NMDR has been the subject of some debate within the area of chemical risk assessment, which is traditionally anchored around driving health-based guidance values for apical endpoints that typically follow a clear monotonic dose–response. The consequence of NMDR for chemical risk assessment has recently received considerable attention amongst regulatory agencies, which confirmed its relevance particularly for receptor-mediated effects. The present review explores the relationship between DEHP exposure and testosterone levels, investigating the biological plausibility of the observed NMDRs. The Adverse Outcome Pathway (AOP) concept is applied to integrate NMDRs into Key Event Relationships (KERs) for exploring a mechanistic understanding of initial key events and possibly associated reproductive and non-reproductive adverse outcomes.