Knotting nets: Molecular junctions of interconnecting endocrine axes identified by application of the adverse outcome pathway concept.

To be defined as an endocrine disruptor, a substance has to meet several criteria, including the induction of specific adverse effects, a specific endocrine mode of action, and a plausible link between both. The latter criterion in particular might not always be unequivocally determined, especially because the endocrine system consists of diverse endocrine axes. The axes closely interact with each other, and manipulation of one triggers effects on the other. The present review aimed to identify some of the many interconnections between these axes. The focus was on fish, but data obtained in studies on amphibians and mammals were considered if they assisted in closing data gaps, because most of the endocrine mechanisms are evolutionarily conserved. The review includes data both from ecotoxicological studies and on physiological processes and gives information on hormone/hormone receptor interactions or gene transcription regulation. The key events and key event relationships identified provide explanations for unexpected effects on one axis, exerted by substances suspected to act specifically on another axis. Based on these data, several adverse outcome pathway (AOP) segments are identified, describing connections between the hypothalamic-pituitary-gonadal (HPG) and hypothalamic-pituitary-thyroid (HPT) axes, the HPG and hypothalamic-pituitary-adrenal/interrenal (HPA/I) axes, and the HPT and HPA/I axes. Central key events identified across axes were altered aromatase activity as well as altered expression and function of the proteins 11ß-hydroxysteroid dehydrogenase (11ß-HSD) and steroidogenic acute regulatory (StAR) protein. Substance classes that act on more than one endocrine axis were, for example, goitrogens or aromatase inhibitors. Despite the wealth of information gathered, the present review only provides a few insights into the molecular nets of endocrine axes, demonstrating the complexity of their interconnections. Environ Toxicol Chem 2018;37:318-328. © 2017 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.

Ecotoxicological characterisation and classification of existing chemicals. Examples from the ICCA HPV initiative and comparison with other existing chemicals.

GOAL, SCOPE AND BACKGROUND: In 1998, the International Council of Chemical Associations (ICCA) launched a global initiative to investigate more than 1,000 HPV chemicals (High Production Volume, > or = 1,000 t/a) within the refocused OECD HPV Chemicals Programme. Up to the OECD SIDS Initial Assessment Meeting in April 2004 (SIAM 18) 147 ICCA dossiers (ca. 230 CAS-No) have been assessed based on a harmonised data set. The environmental profile and an ecotoxicological characterisation of these chemicals are presented here. Data for acute aquatic toxicity were correlated among each other, as well as data for fish (LC50, LD50) and rodents (LD50). The data for acute aquatic toxicity are compared with other existing chemicals. METHODS: Data of the ICCA HPV chemicals from the OECD SIAM 11-18 are presented for: log Kow (as an indicator for bioaccumulation potential), biodegradation, acute aquatic toxicity and availability of long-term toxicity data. Correlation analysis was performed with log transformed data and a linear regression model was fitted to the data, if a significant correlation was found. Acute toxicity for fish and acute oral toxicity for rodents were correlated on a molar basis. Acute aquatic toxicity of the chemicals is compared with data from BUA reports 1-234 and a random EINECS sample (Knacker et al. 1995). RESULTS AND DISCUSSION: According to the dossier information, 71 of the 147 ICCA chemicals are not 'readily biodegradable', 21 have a log Kow > or = 3, and 44 are 'toxic' (LC/EC50 < or = 10 mg/L) or 'very toxic' (LC/EC50 < or = 1 mg/L) to aquatic organisms. For 77, only the base set (acute fish, Daphnia and algae) is available, for the rest at least one long-term test (fish or Daphnia) is available and three tests for a mere 14 others. Based on the data presented, the SIAM gives recommendations for Environment and Human Health. 22 chemicals have been identified as a 'candidate for further work' for Environment and 16 for Human Health. The highest correlation coefficient was obtained correlating fish and Daphnia (r2 = 0.79). LC50 (fish) is significantly correlated with LD50 (rodent), but data are widely scattered. The correlation is not improved after transforming LC50 (fish) to LD50 (fish), using BCF QSAR. Based on acute aquatic toxicity, 25.1% of the chemicals from the BUA reports 1-234 are classified as 'very toxic' (LC/EC50 < or = 1 mg/L). This proportion is 2.5-fold higher than the ICCA HPV chemicals and 1.4-fold higher than the random EINECS sample. CONCLUSIONS: Correlation coefficients for aquatic toxicity data are rather uniform (0.57-0.79) compared with literature data, but also the best correlation was observed between fish and Daphnia. Because the scatter around the regression lines is still considerable, simple predictions of ecotoxicity between species are not possible. Correlation of LC50 (fish) and LD50 (rodent) indicates that toxicity is different. Surprisingly, the correlation of fish and rodent toxicity is not improved by transforming LC50 values to internal LD50s. The selection of ICCA chemicals by market significance (production volume) leads to a classification of toxicity, which is more comparable to a random sample of EINECS chemicals than to German BUA chemicals. The latter were chosen for concern (for Environment or Human Health). RECOMMENDATIONS AND OUTLOOK: Of 147 dossiers assessed between SIAM 11-18, ca. 75% were sponsored by the three following countries: Germany (42), USA (37) and Japan (33). The current output is about 50 dossiers per year (70-100 CAS-No), but a trend for an increase of output is noticeable. Industry, national authorities, and OECD work on a further development to speed up the output. The number of chemicals with 'low priority for further work' and the work recommended for the 'candidates' (mainly exposure assessment) indicate that the data presented were adequate for an initial hazard assessment according to OECD requirements. From the ICCA HPV list (n = 880, state of 1999) 44% of the chemicals have data available to cover all SIDS endpoints for Environment and only 33% for Human Health (Allanou et al. 1999). This indicates the importance of the Initiative to provide information on existing chemicals. The authors agree with the expectation "...that the scientific information provided by this global initiative will be considered as an internationally accepted and harmonised basis for further steps of chemicals management." (ICCA 2002 b).

Long-term effects of fenoxycarb on two mayfly species in artificial indoor streams.

The effects of the juvenile hormone analog fenoxycarb (CAS No. 72490-01-8) were investigated in artificial indoor streams. The results from aufwuchs and two mayfly species (Rhithrogena semicolorata and Ephemerella ignita) are presented. Four concentrations ranging from 0.05 to 50 microg/L (with a spacing factor of 10) were tested. Fenoxycarb disappeared rapidly from the water phase (DT(50) approximately 5 days in the highest concentration, less in the other concentrations). Physico-chemical parameters and aufwuchs were not affected by fenoxycarb. The mayfly R. semicolorata, introduced at the start of the experiment, was affected by treatments of 5 and 50 microg/L. For the larvae in the streams a LC(50) of 3.3 microg/L and for the larvae in the enclosures a LC(50) of 2.5 microg/L were calculated. The second species (E. ignita) was introduced 72 days after the application, at which time no fenoxycarb was detectable in the water of the streams (limit of detection of 0.5 ng/L). The emergence of E. ignita was affected in the highest treatment (50 microg/L). Ninety percent of the emerged imagoes showed morphological abnormalities at the abdomen.

Bisphenol-A in artificial indoor streams: I. Fate and effects on aufwuchs.

The disappearance (DT50) from water-phase and effects on aufwuchs of three nominal concentrations (5, 50 and 500 microg/l) of bisphenol-A (BPA) were investigated in artificial indoor streams over a period of 103 days. HPLC was used for analyses of BPA in water. Because of the disappearance of BPA from the water-phase, a pulse dosed exposure in weekly intervals was established. At the beginning of the exposure, a lag-phase of approximately 3-8 days was noted. Afterwards DT50 values (time, when 50% of initial BPA disappeared) were about 1 day with no clear trend to lower values during the experiment. The dynamics of aufwuchs was investigated on artificial substrates (unglazed ceramic tiles) in 14-day intervals and quantified by ash free dry weight (AFDW). As an ecotoxicological endpoint the area under the biomass/time curve (AUC) was calculated for: (a) the absolute AFDW-values and (b) values as percentage of start biomass (value of day-2 set as 100%). The reduction of AUC by 10% (EC10) and 50% (EC50) for absolute values was 11 microg/l (nominal: 38) and 46 microg/l (450), respectively; for values as percentage of start biomass: EC10 20 microg/l (239) and EC50 73 microg/l (806). These values are 20-70-fold lower compared to results from standard algae tests (EbC, 96 h).