TY - JOUR
T1 - From single chemicals to mixtures-Reproductive effects of levonorgestrel and ethinylestradiol on the fathead minnow
AU - Runnalls, Tamsin J.
AU - Beresford, Nicola
AU - Kugathas, Subramaniam
AU - Margiotta-Casaluci, Luigi
AU - Scholze, Martin
AU - Scott, Alexander P.
AU - Sumpter, John P.
N1 - Funding Information:
The authors wold like to thank members of the Ecotoxicology Research Group, Brunel University London, particularly Julie Walker and Steve Pash, for fish husbandry, and Scott Ellis for his invaluable help during the experiments. Thanks must also go to Ioanna Katsiadaki for helpful discussions with the interpretation of some of the results. This research was conducted under a Department of the Environment, Food and Rural affairs (DEFRA, UK) research contract. L.M.-C. was supported by a Biotechnology and Biological Sciences Research Council (BBSRC) Research Grant (BB/100646X/1) awarded to J.P.S.
Publisher Copyright:
© 2015 Z. Published by Elsevier B.V.
PY - 2015/12/1
Y1 - 2015/12/1
N2 - The aquatic environment is polluted with thousands of chemicals. It is currently unclear which of these pose a significant threat to aquatic biota. The typical exposure scenario is now represented by a widespread blanket of contamination composed of myriads of individual pollutants-each typically present at a low concentration. The synthetic steroids, 17α-ethinylestradiol and levonorgestrel, have been widely reported to be present in the aquatic environment in the low ng to sub-ng/l range. They are widely used in contraceptive formulations, both individually and in combination. Our research employed the fathead minnow (Pimephales promelas) 21 day 'pair-breeding' assay to assess reproductive output when pairs of fish were exposed to the single chemicals at low environmentally relevant concentrations, and then to a binary mixture of them. A variety of endpoints were assessed, including egg production, which was inhibited in a concentration-dependent manner by both the individual chemicals and the mixture. Significant, sex specific effects were also seen with both chemicals, at differing levels of biological organisation. Plasma concentrations of EE2 and levonorgestrel were predicted and in the case of levonorgestrel measured, and compared with the human therapeutic plasma concentrations (Read-Across approach) to support the interpretation of the results. A novel quantitative method was developed for the data analysis, which ensured a suitable endpoint for the comparative mixture assessment. This approach compares the reproductive performance from individual pairs of fish during chemical exposure to its pre-treatment performance. The responses from the empirical mixture study were compared to predictions derived from the single substance data. We hypothesised combined responses which were best described by the concept of concentration addition, and found no clear indications against this additivity expectation. However, the effect profiles support the current knowledge that both compounds act in different ways to reduce egg production in fish, and suggest that probably response addition (also called Independent action) is the more appropriate mixture model in this case.
AB - The aquatic environment is polluted with thousands of chemicals. It is currently unclear which of these pose a significant threat to aquatic biota. The typical exposure scenario is now represented by a widespread blanket of contamination composed of myriads of individual pollutants-each typically present at a low concentration. The synthetic steroids, 17α-ethinylestradiol and levonorgestrel, have been widely reported to be present in the aquatic environment in the low ng to sub-ng/l range. They are widely used in contraceptive formulations, both individually and in combination. Our research employed the fathead minnow (Pimephales promelas) 21 day 'pair-breeding' assay to assess reproductive output when pairs of fish were exposed to the single chemicals at low environmentally relevant concentrations, and then to a binary mixture of them. A variety of endpoints were assessed, including egg production, which was inhibited in a concentration-dependent manner by both the individual chemicals and the mixture. Significant, sex specific effects were also seen with both chemicals, at differing levels of biological organisation. Plasma concentrations of EE2 and levonorgestrel were predicted and in the case of levonorgestrel measured, and compared with the human therapeutic plasma concentrations (Read-Across approach) to support the interpretation of the results. A novel quantitative method was developed for the data analysis, which ensured a suitable endpoint for the comparative mixture assessment. This approach compares the reproductive performance from individual pairs of fish during chemical exposure to its pre-treatment performance. The responses from the empirical mixture study were compared to predictions derived from the single substance data. We hypothesised combined responses which were best described by the concept of concentration addition, and found no clear indications against this additivity expectation. However, the effect profiles support the current knowledge that both compounds act in different ways to reduce egg production in fish, and suggest that probably response addition (also called Independent action) is the more appropriate mixture model in this case.
KW - EE2
KW - Fathead minnow
KW - Levonorgestrel
KW - Mixtures toxicity
KW - Read-Across
KW - Reproduction
UR - http://www.scopus.com/inward/record.url?scp=84946552413&partnerID=8YFLogxK
U2 - 10.1016/j.aquatox.2015.10.009
DO - 10.1016/j.aquatox.2015.10.009
M3 - Article
C2 - 26551686
AN - SCOPUS:84946552413
SN - 0166-445X
VL - 169
SP - 152
EP - 167
JO - AQUATIC TOXICOLOGY
JF - AQUATIC TOXICOLOGY
ER -
