Which chemicals should be grouped together for mixture risk assessments of male reproductive disorders?

There is concern about cumulative exposures to compounds that disrupt male sexual differentiation in foetal life, leading to irreversible effects in adulthood, including declines in semen quality, testes non-descent, malformations of the penis and testis cancer. Traditional chemical-by-chemical risk assessment approaches cannot capture the likely cumulative health risks. Past efforts of focusing on combinations of phthalates, a subgroup of chemicals suspected of contributing to these risks, do not go far enough, as they ignore the contribution of other types of chemicals. With the aim of providing criteria for the inclusion of additional chemicals in mixture risks assessments for male reproductive health, this paper examines the mechanisms of action of various chemicals capable of disrupting male sexual differentiation. An Adverse Outcome Pathway (AOP) network for malformations of the male reproductive system is constructed that includes new findings about the role of disruptions of prostaglandin signalling. This network is used to identify pathways that converge at critical nodal points to produce down-stream adverse effects. From this knowledge, combinations of chemicals with different mechanisms of action are predicted that should result in cumulative effects. These predictions are then mapped against evidence from experimental mixture studies with relevant combinations. From the outcome of this analysis it is concluded that cumulative assessment groups for male reproductive health risks should not only include phthalates but also comprise androgen receptor (AR) antagonists, chemicals capable of disrupting steroid synthesis, InsL3 production, prostaglandin signalling and co-planar polychlorinated dibenzo-dioxins together with other dioxin-like compounds. This list goes far beyond what has been suggested previously. A minimum set of chemicals to be assessed together with phthalates includes pesticides such as vinclozolin, prochloraz, procymidone, linuron, the pain killers paracetamol, aspirin and ibuprofen, pharmaceuticals such as finasteride, ketoconazole, and the lipid-lowering drug simvastin, poly-chlorinated dibenzo-dioxins and other dioxin-like pollutants and phenolics such as bisphenol A and butylparaben. AOP network analyses are essential to overcome difficulties in establishing groupings of chemicals for mixture risk assessments that derive from a narrow focus on mechanisms and modes of action.