Mixtures of endocrine-disrupting contaminants induce adverse developmental effects in preweaning rats

Abstract

Reproductive toxicity was investigated in rats after developmental exposure to a mixture of 13 endocrine-disrupting contaminants, including pesticides, plastic and cosmetic ingredients, and paracetamol. The mixture was composed on the basis of information about high-end human exposures, and the dose levels reflecting 100, 200, and 450 times this exposure were tested. The compounds were also grouped according to their estrogenicity or anti-androgenicity, and their joint effects were tested at two different doses, with each group reflecting 200 or 450 times human exposure. In addition, a single paracetamol dose was tested (350 mg/kg per day). All exposures and a vehicle were administered by oral gavage to time-mated Wistar dams rats throughout gestation and lactation, and their offspring were assessed for reproductive effects at birth and in prepuberty. The mixture doses, which included the anti-androgenic compounds, affected the male offspring by causing decreased anogenital distance, increased nipple retention (NR), and reduced ventral prostate weights, at both medium and high doses. In addition, the weights of the levator ani/bulbocavernosus muscle (LABC) were decreased at the high dose of anti-androgen mixture. No effects were seen after exposure to the estrogenic chemicals alone, whereas males exposed solely to paracetamol showed decreased LABC weights and increased NR. Thus adverse reproductive effects were observed at mixtures reflecting 200 times high-end human exposure, which is relatively close to the safety margin covered by the regulatory uncertainty factor of 100. This suggests that highly exposed human population groups may not be sufficiently protected against mixtures of endocrine-disrupting chemicals.

Biomonitoring of Danish school children and mothers including biomarkers of PBDE and glyphosate

“…However, the population is exposed to a mixture of many chemicals simultaneously and the health effects might therefore be a result of the total exposure to multiple chemicals. The health effects of mixtures of chemicals may not be the sum of the individual effects, which has been shown in animal studies (4,5).…”

Assessing the impact of in-utero exposures: potential effects of paracetamol on male reproductive development

“…AGD was reduced in male offspring compared with untreated controls30 with similar effects on AGD described in other studies 38 77. However, a recent study using the same regimen as described above (350 mg/kg/day from e13 to e21) did not demonstrate a significant effect on AGD 76. The timing of exposure in these studies coincides with the MPW; however, the doses (150–350 mg/kg/day) used are higher than therapeutic doses (~60 mg/kg/day) to which humans are usually exposed 38.…”

Cumulative effects of antiandrogenic chemical mixtures and their relevance to human health risk assessment

“…Furthermore, the laboratories of Ulla Hass and Andreas Kortenkamp have corroborated our observations that dose addition accurately predicts the effects of mixtures of antiandrogenic chemicals on androgen-dependent reproductive development, regardless of whether the individual chemical share a mechanism of action or not (Christiansen et al, 2009; Hass et al, 2007; Metzdorff et al, 2007; Orton et al, 2014; Orton et al, 2012). They also report that mixtures of endocrine disrupting chemicals combined at environmentally-relevant dose levels induce effects greater than expected based on individual chemical doses levels (Axelstad et al, 2014; Isling et al, 2014). Research on mixtures of antiandrogens and other combinations of endocrine-disrupting chemicals is an important area of study that, in combination with human biomonitoring, will inform more accurate cumulative risk assessments to preserve human reproductive health.…”