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Cumulative Effects of Antiandrogenic Chemical Mixtures and Their Relevance to Human Health Risk Assessment

Kembra L. Howdeshell, Andrew K. Hotchkiss, L. Earl Gray Jr.
International Journal of Hygiene and Environmental Health (2017) DOI: https://doi.org/10.1016/j.ijheh.2016.11.007 PMID: 27923611



Toxicological studies of defined chemical mixtures assist human health risk assessment by establishing how chemicals interact with one another to induce an effect. This paper reviews how antiandrogenic chemical mixtures can alter reproductive tract development in rats with a focus on the reproductive toxicant phthalates. The reviewed studies compare observed mixture data to mathematical mixture model predictions based on dose addition or response addition to determine how the individual chemicals in a mixture interact (e.g., additive, greater, or less than additive). Phthalate mixtures were observed to act in a dose additive manner based on the relative potency of the individual phthalates to suppress fetal testosterone production. Similar dose additive effects have been reported for mixtures of phthalates with antiandrogenic pesticides of differing mechanisms of action. Overall, data from these phthalate experiments in rats can be used in conjunction with human biomonitoring data to determine individual hazard indices, and recent cumulative risk assessments in humans indicate an excess risk to antiandrogenic chemical mixtures that include phthalates only or phthalates in combination with other antiandrogenic chemicals.


Figure 1. Adverse outcome pathway network for disrupted androgen- and insulin-like hormone 3.

Adverse outcome pathway network for disrupted androgen- and insulin-like hormone 3 (INSL3)-dependent reproductive development in male rats. The first column of the AOP network identifies three classes of chemicals known to disrupt the androgen-signaling pathways via three different mechanisms of action. Different colored arrows indicate the pathway through which each set of chemicals exerts its affects: gray arrows, androgen receptor (AR antagonists); green stripped arrows, dual mechanism of action chemicals (AR antagonists and steroid enzyme inhibitors); and red checkered arrows, phthalates (molecular initiating event unknown, but known to inhibit fetal testosterone (T) production). *Reproductive toxicant effects of phthalates are not mediated via the AR or the peroxisome proliferator activated receptor alpha (PPARĪ±). **INSL3 hormone is required for maturation of the gubernacular cords, which leads to transabdominal descent of the testes (the first phase of testes descent).


Table 1. List of chemical mixtures targeting male reproductive development.

List of chemical mixtures targeting male reproductive development in the Earl Gray, Jr. laboratory, USEPA (as of October 2016).