Endocrine Abstracts

Risk assessment of chemicals based on no observed adverse effect level (NOAEL) from animal models is normally done for one chemical at a time, but several endocrine disrupting chemicals (EDCs) have been detected in mixtures in humans.

For combinations of EDCs with similar mechanism, there is clear evidence that mixture effects can arise at doses around NOAELs. Also, the mixture effects can be predicted based on dose-addition.

There is also good evidence that combinations of EDCs with diverse modes of androgen action, but similar effects induce mixture effects when each component is present at doses equal to NOAELs. We have investigated mixtures of a widely used plasticizer, di(2-ethylhexyl) phthalate (DEHP); two fungicides, vinclozolin and prochloraz; and a pharmaceutical, finasteride for effects on male sexual development in the rat. When the four chemicals were combined at doses equal to their NOAEL, significantly reduced anogenital distance (AGD) was observed in male offspring. Surprisingly, the effect of combined exposure on malformations of external sex organs was synergistic. For effects on AGD, retained nipples, and sex organ weights, the combined effects were dose additive.

We have also studied effects of mixtures modelled based on high end human intakes. We selected 13 EDCs where data about human exposures was available, including phthalates, pesticides, UV-filters, bisphenol A, parabens and the drug paracetamol. The results suggest that highly exposed women of reproductive age may not be protected sufficiently against the combined effects of EDCs that affect the hormonal milieu required for normal sexual differentiation of male foetuses.

In conclusion, the chemical-by-chemical approach in risk assessment appears as insufficiently protective against the possibility of mixture effects. In most cases the mixture effects were dose additive. Thus, cumulative risk assessment for endocrine disrupters is both relevant and feasible and dose addition as an assessment method is recommended.