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Introduction
In chemical hazard characterizations for pesticides, biocides, and other potentially toxic chemicals, single substances are tested in relevant animal studies with the aim of estimating exposures that are without apparent effects. These estimates form the basis for deriving human reference doses commonly regarded as safe levels of exposure. Normally, this exercise is conducted by considering one chemical at a time, but this single chemical approach does not account for the possibility that simultaneous exposures to other chemicals may also contribute to the toxicity under consideration. As a consequence, single chemical exposures judged to be safe in isolation may in reality pose significant risks, if there is co-exposure to mixtures of substances with similar toxicities. However, the impact of not considering such co-exposures on risk estimates as well as the relevance of co-exposures on the safe use of drugs remains poorly defined.
Potentially higher risks of mixtures need to be taken into account, particularly when the health effects are irreversible, such as those arising from disrupting the action of hormones during key stages of development. Here we investigate the combined effects of chemicals that interfere with androgen action in human testicular tissue. During the first trimester of pregnancy, fetal androgens play a key role in the development and growth of the male reproductive tract, specifically by regulating testicular descent, penile development, and organization of seminiferous tubules (Huhtaniemi 1994). Animal toxicology studies and human epidemiology studies have shown that disruption of androgen action at this time can have irreversible consequences at birth, including testis maldescent (cryptorchidism) and penile malformations where the urethral opening is placed on the underside of the penis (hypospadias). Analysis of secular trends in humans have revealed increasing prevalence of these disorders in some industrialized countries; furthermore, cryptorchidism and hypospadias are increased risk factors for testicular cancer (Cook et al. 2010; Serrano et al. 2013; Skakkebaek et al. 2016).
Numerous chemicals have been identified as antiandrogens in experimental animals and cell-based systems and have been shown to induce androgen insufficiency by several modes of action: suppressing androgen synthesis, blocking the androgen receptor, or altering the signaling of local mediators such as prostaglandins. Prominent examples of anti-androgenic chemicals include certain phthalates used as plasticizers, pesticides, and mild analgesics (Albert and Jégou 2014; Ben Maamar...