Abstract
Humans are concomitantly exposed to numerous chemicals. An infinite number of combinations and doses thereof can be imagined. For toxicological risk assessment the mathematical prediction of mixture effects, using knowledge on single chemicals, is therefore desirable. We investigated pros and cons of the concentration addition (CA), independent action (IA) and generalized concentration addition (GCA) models. First we measured effects of single chemicals and mixtures thereof on steroid synthesis in H295R cells. Then single chemical data were applied to the models; predictions of mixture effects were calculated and compared to the experimental mixture data. Mixture 1 contained environmental chemicals adjusted in ratio according to human exposure levels. Mixture 2 was a potency adjusted mixture containing five pesticides. Prediction of testosterone effects coincided with the experimental Mixture 1 data. In contrast, antagonism was observed for effects of Mixture 2 on this hormone. The mixtures contained chemicals exerting only limited maximal effects. This hampered prediction by the CA and IA models, whereas the GCA model could be used to predict a full dose response curve. Regarding effects on progesterone and estradiol, some chemicals were having stimulatory effects whereas others had inhibitory effects. The three models were not applicable in this situation and no predictions could be performed. Finally, the expected contributions of single chemicals to the mixture effects were calculated. Prochloraz was the predominant but not sole driver of the mixtures, suggesting that one chemical alone was not responsible for the mixture effects. In conclusion, the GCA model seemed to be superior to the CA and IA models for the prediction of testosterone effects. A situation with chemicals exerting opposing effects, for which the models could not be applied, was identified. In addition, the data indicate that in non-potency adjusted mixtures the effects cannot always be accounted for by single chemicals.
Highlights
Most humans are concomitantly exposed to multiple chemicals at any given point in time [1,2]
The Concentration addition (CA) and Independent action (IA) models are driven by a single chemical if this single chemical exists in a concentration not very different from the other chemicals and has a potency that is substantially higher than the other members of the mixture
Prochloraz seems to be the chemical driving the effect on steroidogenesis of two environmental chemical mixtures, in some cases the presence of other chemicals diminished its expected contribution
Summary
Most humans are concomitantly exposed to multiple chemicals at any given point in time [1,2]. It is impossible to test every chemical combination, it is desirable to be able to predict effects of mixtures from the knowledge on effects of single chemicals For this purpose, a range of mathematical models have been developed. Concentration addition (CA), called dose addition, was introduced by Loewe and Muischneck [4] This model is based on a dilution principle, and was designed for chemicals with a similar mechanism of action, and has proven effective in several settings [5,6]. Even when the models are challenged with chemicals having different mechanisms of action and chemicals mixed according to their potency to exert equal effects, the difference in prediction by IA and CA does not exceed a factor of five [8,9] This relatively minor difference suggests that either model may be sufficient for risk assessment purposes. This model has proven effective in calculating mixture effects of aryl hydrocarbon receptor agonists [10,11]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
