Ten Years of Mixing Cocktails: A Review of Combination Effects of Endocrine-Disrupting Chemicals

In the last 10 years, good evidence has become available to show that the combined effects of endocrine disruptors (EDs) belonging to the same category (e.g., estrogenic, antiandrogenic, or thyroid-disrupting agents) can be predicted by using dose addition. This is true for a variety of end points representing a wide range of organizational levels and biological complexity. Combinations of EDs are able to produce significant effect, even when each chemical is present at low doses that individually do not induce observable effects. However, comparatively little is known about mixtures composed of chemicals from different classes of EDs. Nevertheless, I argue that the accumulated evidence seriously undermines continuation with the customary chemical-by-chemical approach to risk assessment for EDs. Instead, we should seriously consider group-wise regulation of classes of EDs. Great care should be taken to define such classes by using suitable similarity criteria. Criteria should focus on common effects, rather than common mechanisms. In this review I also highlight research needs and identify the lack of information about exposure scenarios as a knowledge gap that seriously hampers progress with ED risk assessment. Future research should focus on investigating the effects of combinations of EDs from different categories, with considerable emphasis on elucidating mechanisms. This strategy may lead to better-defined criteria for grouping EDs for regulatory purposes. Also, steps should be taken to develop dedicated mixtures exposure assessment for EDs.

[1]  C. I. Bliss THE TOXICITY OF POISONS APPLIED JOINTLY1 , 1939 .

[2]  M C Berenbaum,et al.  Criteria for analyzing interactions between biologically active agents. , 1981, Advances in cancer research.

[3]  T. Umbreit,et al.  Interactive effects of estradiol and 2,3,7,8-tetrachlorodibenzo-p-dioxin on hepatic cytochrome P-450 and mouse uterus. , 1986, Toxicology letters.

[4]  M. Romkes,et al.  Effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin on hepatic and uterine estrogen receptor levels in rats. , 1987, Toxicology and applied pharmacology.

[5]  S. Safe,et al.  Comparative antiestrogenic activities of 2,3,7,8-tetrachlorodibenzo-p-dioxin and 6-methyl-1,3,8-trichlorodibenzofuran in the female rat. , 1988, Toxicology and applied pharmacology.

[6]  M. Romkes,et al.  Comparative activities of 2,3,7,8-tetrachlorodibenzo-p-dioxin and progesterone as antiestrogens in the female rat uterus. , 1988, Toxicology and applied pharmacology.

[7]  Berenbaum Mc What is synergy? , 1989, Pharmacological reviews.

[8]  M. Berenbaum What is synergy? , 1989, Pharmacological reviews.

[9]  Stimulation of estrogen receptor-mediated transcription and alteration in the phosphorylation state of the rat uterine estrogen receptor by estrogen, cyclic adenosine monophosphate, and insulin-like growth factor-I. , 1993, Molecular endocrinology.

[10]  Raymond S. H. Yang 1 – Introduction to the Toxicology of Chemical Mixtures , 1994 .

[11]  Raymond S. H. Yang Toxicology of chemical mixtures : case studies, mechanisms, and novel approaches , 1994 .

[12]  Weanling female Sprague-Dawley rats are not sensitive to the antiestrogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). , 1995, Toxicology and applied pharmacology.

[13]  W. Greco,et al.  The search for synergy: a critical review from a response surface perspective. , 1995, Pharmacological reviews.

[14]  K. Korach,et al.  Peptide growth factor cross-talk with the estrogen receptor requires the A/B domain and occurs independently of protein kinase C or estradiol. , 1996, Endocrinology.

[15]  Steven F. Arnold,et al.  Synergistic Activation of Estrogen Receptor with Combinations of Environmental Chemicals , 1996, Science.

[16]  C. A. Harris,et al.  Synergy between synthetic oestrogens? , 1997, Nature.

[17]  Potency of Combined Estrogenic Pesticides , 1997, Science.

[18]  L G Sultatos,et al.  Common mechanism of toxicity: a case study of organophosphorus pesticides. , 1998, Toxicological sciences : an official journal of the Society of Toxicology.

[19]  Safe,et al.  Toxic equivalency factors (TEFs) for PCBs, PCDDs, PCDFs for humans and wildlife. , 1998, Environmental health perspectives.

[20]  S. Safe,et al.  Hazard and risk assessment of chemical mixtures using the toxic equivalency factor approach. , 1998, Environmental health perspectives.

[21]  A. Kortenkamp,et al.  Synergisms with mixtures of xenoestrogens: a reevaluation using the method of isoboles. , 1998, The Science of the total environment.

[22]  A. Kortenkamp,et al.  Prediction and assessment of the effects of mixtures of four xenoestrogens. , 2000, Environmental health perspectives.

[23]  Estrogen enhances induction of cytochrome P-4501A1 by 2,3,7, 8-tetrachlorodibenzo-p-dioxin in liver of female Long-Evans rats. , 2000, International journal of oncology.

[24]  Edward F. Orlando,et al.  Effects of environmental antiandrogens on reproductive development in experimental animals , 2001 .

[25]  S. Safe,et al.  Identification of estrogen-induced genes downregulated by AhR agonists in MCF-7 breast cancer cells using suppression subtractive hybridization. , 2001, Gene.

[26]  J. Furr,et al.  Effects of environmental antiandrogens on reproductive development in experimental animals , 2001, Human reproduction update.

[27]  T. Suzuki,et al.  Response of MCF‐7 human breast cancer cells to some binary mixtures of oestrogenic compounds in‐vitro , 2001, The Journal of pharmacy and pharmacology.

[28]  P. Terranova,et al.  The effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on weight gain and hepatic ethoxyresorufin-o-deethylase (EROD) induction vary with ovarian hormonal status in the immature gonadotropin-primed rat model. , 2001, Reproductive toxicology.

[29]  M. Scholze,et al.  Assessing the biological potency of binary mixtures of environmental estrogens using vitellogenin induction in juvenile rainbow trout (Oncorhynchus mykiss). , 2001, Environmental science & technology.

[30]  A. Kortenkamp,et al.  Mixtures of four organochlorines enhance human breast cancer cell proliferation. , 2001, Environmental health perspectives.

[31]  A. Kortenkamp,et al.  Something from "nothing"--eight weak estrogenic chemicals combined at concentrations below NOECs produce significant mixture effects. , 2002, Environmental science & technology.

[32]  C. Gennings,et al.  An approach for assessing estrogen receptor-mediated interactions in mixtures of three chemicals: a pilot study. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[33]  B. Bhaskar Gollapudi,et al.  Assessment of Interactions of Diverse Ternary Mixtures in an Estrogen Receptor-α Reporter Assay , 2002 .

[34]  J. Haseman,et al.  Summary of the National Toxicology Program's report of the endocrine disruptors low-dose peer review. , 2002, Environmental health perspectives.

[35]  G. Perdew,et al.  The subdomains of the transactivation domain of the aryl hydrocarbon receptor (AhR) inhibit AhR and estrogen receptor transcriptional activity. , 2002, Archives of biochemistry and biophysics.

[36]  A. Kortenkamp,et al.  Combining xenoestrogens at levels below individual no-observed-effect concentrations dramatically enhances steroid hormone action. , 2002, Environmental health perspectives.

[37]  H. Sone,et al.  Interaction between Dioxin Signaling and Sex Steroid Hormones , 2002 .

[38]  E. Calabrese "Effects of subchronic exposure to a complex mixture of persistent contaminants in male rats: systemic, immune and reproductive effects". , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[39]  Assessment of interactions of diverse ternary mixtures in an estrogen receptor-alpha reporter assay. , 2002, Toxicology and applied pharmacology.

[40]  Michel Fournier,et al.  Effects of subchronic exposure to a complex mixture of persistent contaminants in male rats: systemic, immune, and reproductive effects. , 2002, Toxicological sciences : an official journal of the Society of Toxicology.

[41]  L. Birnbaum,et al.  A Mixture of Dioxins, Furans, and Non-ortho PCBs Based upon Consensus Toxic Equivalency Factors Produces Dioxin-Like Reproductive Effects , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[42]  Robert J Kavlock,et al.  Uncertainties for endocrine disrupters: our view on progress. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[43]  M. Scholze,et al.  Relative potencies and combination effects of steroidal estrogens in fish. , 2003, Environmental science & technology.

[44]  L. Marro,et al.  Effects of postnatal exposure to mixtures of non-ortho-PCBs, PCDDs, and PCDFs in prepubertal female rats. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[45]  D. Picard Molecular mechanisms of cross-talk between growth factors and nuclear receptor signaling , 2003 .

[46]  M. Dalgaard,et al.  The combined effects of vinclozolin and procymidone do not deviate from expected additivity in vitro and in vivo. , 2003, Toxicological sciences : an official journal of the Society of Toxicology.

[47]  J. Ashby,et al.  Sensitivity of the immature rat uterotrophic assay to mixtures of estrogens. , 2004, Environmental health perspectives.

[48]  J. G. Vandenbergh,et al.  A Mixture of the “Antiandrogens” Linuron and Butyl Benzyl Phthalate Alters Sexual Differentiation of the Male Rat in a Cumulative Fashion1 , 2004, Biology of reproduction.

[49]  L Earl Gray,et al.  Interactive effects of vinclozolin and testosterone propionate on pregnancy and sexual differentiation of the male and female SD rat. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[50]  Eiji Katsura,et al.  Screening for estrogen and androgen receptor activities in 200 pesticides by in vitro reporter gene assays using Chinese hamster ovary cells. , 2004, Environmental health perspectives.

[51]  A. Kortenkamp,et al.  Deviation from additivity with estrogenic mixtures containing 4-nonylphenol and 4-tert-octylphenol detected in the E-SCREEN assay. , 2004, Environmental science & technology.

[52]  J. Fisher,et al.  Are all EDC effects mediated via steroid hormone receptors? , 2004, Toxicology.

[53]  M. Dalgaard,et al.  The combined antiandrogenic effects of five commonly used pesticides. , 2004, Toxicology and applied pharmacology.

[54]  Daniel Schlenk,et al.  Evaluation of estrogenic activities of aquatic herbicides and surfactants using an rainbow trout vitellogenin assay. , 2005, Toxicological sciences : an official journal of the Society of Toxicology.

[55]  Common Mechanism of Toxicity , 2005 .

[56]  C. Hughes,et al.  An Extensive New Literature Concerning Low-Dose Effects of Bisphenol A Shows the Need for a New Risk Assessment , 2005, Environmental health perspectives.

[57]  M. van den Berg,et al.  Additive estrogenic effects of mixtures of frequently used UV filters on pS2-gene transcription in MCF-7 cells. , 2005, Toxicology and applied pharmacology.

[58]  C. A. Harris,et al.  Accurate Prediction of the Response of Freshwater Fish to a Mixture of Estrogenic Chemicals , 2005, Environmental health perspectives.

[59]  S. Loewe,et al.  Über Kombinationswirkungen , 2005, Naunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie.

[60]  U. Hass,et al.  Antiandrogenic effects in male rats perinatally exposed to a mixture of di(2-ethylhexyl) phthalate and di(2-ethylhexyl) adipate. , 2005, Reproductive toxicology.

[61]  W. H. Carter,et al.  Thyroid-Hormone–Disrupting Chemicals: Evidence for Dose-Dependent Additivity or Synergism , 2005, Environmental health perspectives.

[62]  S. Loewe,et al.  Über Kombinationswirkungen , 1926, Naunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie.

[63]  T. Nikolskaya,et al.  A COMBINED APPROACH TO DRUG METABOLISM AND TOXICITY ASSESSMENT , 2006, Drug Metabolism and Disposition.

[64]  Andreas Kortenkamp,et al.  Breast cancer, oestrogens and environmental pollutants: a re-evaluation from a mixture perspective. , 2006, International journal of andrology.

[65]  M. Scholze,et al.  Assessment of Xenoestrogens Using Three Distinct Estrogen Receptors and the Zebrafish Brain Aromatase Gene in a Highly Responsive Glial Cell System , 2005, Environmental health perspectives.