Cumulative Effects of In Utero Administration of Mixtures of "Antiandrogens" on Male Rat Reproductive Development

MD-72, Endocrinology Branch, Reproductive Toxicology Division, NHEERL, ORD, U.S. Environmental Protection Agency, RTP, North Carolina 27713, USA.
Toxicologic Pathology (Impact Factor: 2.14). 02/2009; 37(1):100-13. DOI: 10.1177/0192623308329478
Source: PubMed


Although risk assessments are typically conducted on a chemical-by-chemical basis, the 1996 Food Quality Protection Act (FQPA) required the Environmental Protection Agency (EPA) to consider cumulative risk of chemicals that act via a common mechanism of toxicity. To this end, we are conducting studies with mixtures to provide a framework for assessing the cumulative effects of "antiandrogenic" chemicals. Rats were dosed during pregnancy with antiandrogens singly or in pairs at dosage levels equivalent to about one half of the ED50 for hypospadias or epididymal agenesis. The pairs include: AR antagonists (vinclozolin plus procymidone), phthalate esters (DBP plus BBP and DEHP plus DBP), a phthalate ester plus an AR antagonist (DBP plus procymidone), and linuron plus BBP. We predicted that each chemical by itself would induce few malformations; however, by mixing any two chemicals together, about 50% of the males would be malformed. All binary combinations produced cumulative, dose-additive effects on the androgen-dependent tissues. We also conducted a mixture study combining seven "antiandrogens" together. These chemicals elicit antiandrogenic effects at two different sites in the androgen signaling pathway (i.e., AR antagonist or inhibition of androgen synthesis). In this study, the complex mixture behaved in a dose-additive manner. Our results indicate that compounds that act by disparate mechanisms of toxicity display cumulative, dose-additive effects when present in combination.

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    • "This means that there is no possibility to predict the effect of mixtures if a compound induced no effect in the concentration range tested. This needs to be considered in the future when elaborating other mathematical models, as there may be effects on living organisms even if each compound is present in a concentration with no effect in case of individual exposure (Altenburger et al., 2000; Hass et al., 2007; Orton et al., 2014; Rajapakse et al., 2002; Rider et al., 2009; Walter et al., 2002). Due to this limitation we were not able to estimate the antiandrogenic activity of the binary mixtures containing PG as one of the components. "
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    • "A previous report has suggested that butyl benzyl phthalate (BBP) and linuron, both possessing anti-androgenic properties, produce dose additive effects on reproductive tract development (Hotchkiss et al., 2004). Similarly, another study involving seven anti-androgenic chemicals including a combination of three phthalates, BBP, dibutyl phthalate (DBP), and di (2-ethylhexyl) phthalate (DEHP) showed cumulative effects on androgen dependent reproductive functions (Rider et al., 2009). However, these dose addition models were already criticized by EPA due to non-congruent dose responses (EPA, 2000). "
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    • "De nombreuses e ´tudes ont tenté de trouver des facteurs de risque. Les plus fréquemment mis en cause et statistiquement significatifs sont d'ordre : vasculaire (petit poids a ` la naissance, prématurité, prée ´clampsie et insuffisance placentaire, gémellité) ; endocrinien, en particulier les perturbateurs endocriniens [1] via la dérégulation du métabolisme lipidique, glucidique et hormonal [2], notamment les médicaments pris avant (fécondation in vitro [FIV]) et pendant la grossesse comme le clomifène, l'hormone folliculo-stimulante (FSH), la progestérone , le diéthylstilbestrol (DES) [3] et les anti-inflammatoires non stéroı¨diens (AINS) [4] ; environnemental [5] (tabagisme, alcoolisme, présence de pesticides dans les eaux, vie non urbaine) ; génétique [6], comme le montrent les antécédents familiaux. Quelles que soient leur fréquence et leur gravité, ces anomalies doivent retenir l'attention du praticien en raison de leur e ´ventuel retentissement psychologique. "
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