Human risk associated with exposure to mixtures of antiandrogenic chemicals evaluated using in vitro hazard and human biomonitoring data.

BACKGROUND: Scientific evidence for underestimated toxicity from unintentional exposure to chemical mixtures is mounting. Yet, harmonized approaches on how to assess the actual risk of mixtures is lacking. As part of the European Joint programme 'Human Biomonitoring for Europe' we explored a novel methodology for mixture risk assessment of chemicals affecting male reproductive function. METHODOLOGY: We explored a methodology for chemical mixture risk assessment based on human in vitro data combined with human exposure data, thereby circumventing the drawbacks of using hazard data from rodents and estimated exposure intake levels. Human androgen receptor (hAR) antagonism was selected as the most important molecular initiating event linked to adverse outcomes on male reproductive health. RESULTS: Our work identified 231 chemicals able to interfere with hAR activity. Among these were 61 finally identified as having both reliable hAR antagonist and human biomonitoring data. Calculation of risk quotients indicated that PCBs (118, 138, 157), phthalates (BBP, DBP, DIBP), benzophenone-3, PFOS, methylparaben, triclosan, some pesticides (i.e cypermethrin, ß-endosulfan, methylparathion, p,p-DDE), and a PAH metabolite (1-hydroxypyrene) contributed to the mixture effect. The major chemical mixture drivers were PCB 118, BBP, PFOS, DBP, and the UV filter benzophenone-3, together contributing with 75% of the total mixture effect that was primarily driven by high exposure values. CONCLUSIONS: This viable way forward for mixture risk assessment of chemicals has the advantages of (1) being a more comprehensive mixture risk assessment also covering data-poor chemicals, and (2) including human data only. However, the approach is subjected to uncertainties in terms of in vitro to in vivo extrapolation, it is not ready for decision making, and needs further development. Still, the results indicate a concern for adverse effects on reproductive function in highly exposed boys, especially when considering additional exposure to data-poor chemicals and chemicals acting by other mechanisms of action.

On the Use and Interpretation of Areola/Nipple Retention as a Biomarker for Anti-androgenic Effects in Rat Toxicity Studies.

Areola/nipple retention (NR) is an established biomarker for an anti-androgenic mode of action in rat toxicity studies. It is a mandatory measurement under several OECD test guidelines and is typically assessed in combination with anogenital distance (AGD). Both NR and AGD are considered retrospective biomarkers of insufficient androgen signaling during the masculinization programming window in male fetuses. However, there are still aspects concerning NR as a biomarker for endocrine disruption that remains to be clarified. For instance, can NR be regarded a permanent adverse effect? Is it a redundant measurement if AGD is assessed in the same study? Is NR equally sensitive and specific to anti-androgenic chemical substances as a shortening of male AGD? In this review we discuss these and other aspects concerning the use of NR as a biomarker in toxicity studies. We have collected available literature from rat toxicity studies that have reported on NR and synthesized the data in order to draw a clearer picture about the sensitivity and specificity of NR as an effect biomarker for an anti-androgenic mode of action, including comparisons to AGD measurements. We carefully conclude that NR and AGD in rats for the most part display similar sensitivity and specificity, but that there are clear exceptions which support the continued assessment of both endpoints in relevant reproductive toxicity studies. Available literature also support the view that NR in infant male rats signifies a high risk for permanent nipples in adulthood. Finally, the literature suggests that the mechanisms of action leading from a chemical stressor event to either NR or short AGD in male offspring are overlapping with respect to canonical androgen signaling, yet differ with respect to other mechanisms of action.

The impact of dietary habits on contaminant exposures.

This study shows that dietary habits have an impact on contaminant exposures. A tool was developed to calculate chemical exposures for different Danish population groups. First, the tool divided the individuals into quartiles using a previously developed scoring system for how well their diet complies with the Danish dietary guidelines. Then the exposure was calculated for several contaminants for both children and adults within the quartiles. Comparisons were then performed between the exposures for the lowest and highest quartiles. The individuals having a diet more in compliance with the dietary guidelines have a higher exposure to contaminants than individuals having a diet less in compliance with the dietary guidelines. Standard deviations for the mean exposure were in general large indicating that the consumption patterns can be very different within each population group. A risk characterisation for each contaminant and population group was performed by calculation of Hazard Quotients (HQs). For dioxins and dioxin-like polychlorinated biphenyls (PCDD/F + DL-PCBs), inorganic arsenic, and lead all HQs were above 1 indicating a potential risk for all groups. For hexabromocyclododecane (HBCDD) and nickel, a potential risk was identified for at least one group. For all other contaminants the HQs were well below 1 for all groups.