Refined reference doses and new procedures for phthalate mixture risk assessment focused on male developmental toxicity.

New procedures for phthalate mixture risk assessments (MRAs) focused on male developmental toxicity (anti-androgenicity) are overdue. Previous efforts suffer from several shortcomings: There is a lack of consistency in terms of the phthalates entered into the assessments, and in the choice of tolerable intakes. Many of these values do not reflect new evidence about low dose male developmental effects. Nearly all previous mixture risk assessments have focused solely on phthalates, with no regard for exposures to other chemicals that also induce male developmental toxicity, leading to underestimations of risks. Here, we address these weaknesses and inconsistencies by proposing criteria for the selection of phthalates for MRA based on structure-activity relationships. We suggest new reference doses for phthalates for use in MRA, as follows: DBP 6.7 μg/kg/d, DIBP 100 μg/kg/d, BBP 10 μg/kg/d, DEHP 10 μg/kg/d, DINP 59 μg/kg/d. We conclude that the fixation on the Hazard Index (HI) = 1 as signalling acceptable combined phthalate exposures is misguided as it ignores co-exposure to other anti-androgenic chemicals that also contribute to male developmental risks. Until more comprehensive assessments of phthalates in combination with other anti-androgens become feasible, we propose the use of a HI of 0.1-0.2 as a benchmark for interpreting phthalate mixture risk assessments.