Critical analysis of literature on low-dose synergy for use in screening chemical mixtures for risk assessment.
ABSTRACT There is increasing interest in the use of tiered approaches in risk assessment of mixtures or co-exposures to chemicals for prioritization. One possible screening-level risk assessment approach is the threshold of toxicological concern (TTC). To date, default assumptions of dose or response additivity have been used to characterize the toxicity of chemical mixtures. Before a screening-level approach could be used, it is essential to know whether synergistic interactions can occur at low, environmentally relevant exposure levels. Studies demonstrating synergism in mammalian test systems were identified from the literature, with emphasis on studies performed at doses close to the points of departure (PODs) for individual chemicals. This search identified 90 studies on mixtures. Few included quantitative estimates of low-dose synergy; calculations of the magnitude of interaction were included in only 11 papers. Quantitative methodology varied across studies in terms of the null hypothesis, response measured, POD used to test for synergy, and consideration of the slope of the dose-response curve. It was concluded that consistent approaches should be applied for quantification of synergy, including that synergy be defined in terms of departure from dose additivity; uniform procedures be developed for assessing synergy at low exposures; and the method for determining the POD for calculating synergy be standardized. After evaluation of the six studies that provided useful quantitative estimates of synergy, the magnitude of synergy at low doses did not exceed the levels predicted by additive models by more than a factor of 4.
SourceAvailable from: Erminio Giavini[Show abstract] [Hide abstract]
ABSTRACT: The most relevant issues in cumulative risk assessment (CRA) are the identification of cumulative assessment groups and the hypothesis of dose-additivity, at relevant human exposures. In vitro methods can provide meaningful data to help solving those issues. Integration of in vitro studies, selected in vivo studies, and PBPK modeling for teratogenic conazoles confirmed that in vitro studies may give results in a cheaper and faster fashion. In particular, in vitro studies with explanted rat embryos provided support for dose-additivity for conazoles causing cranio-facial malformations. Although this could not be immediately quantitatively transferred to the in vivo situation, they provided indication on how to conduct targeted in vivo studies. In addition, by means of PBPK modeling, it was possible to estimate the dose in humans associated with a defined teratogenic risk and also to conclude that for cumulative risk assessment only exposures occurring within a short period of time (a day or less) need to be cumulated. Although PBPK modeling cannot be widely applied, at least in the short term, it should be considered if available. It is recommended to incorporate in vitro testing and PBPK modeling, whenever available and feasible in the process of risk assessment, particularly of CRA.Food and Chemical Toxicology 07/2014; DOI:10.1016/j.fct.2014.07.006 · 2.61 Impact Factor
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ABSTRACT: The presence of pharmaceuticals in drinking water is a topic of concern. Previous risk assessments indicate that their low concentrations are very unlikely to pose risks to human health, however often conclusions had to be based on small datasets and mixture effects were not included. The objectives of this study were to a) investigate if pharmaceuticals in surface and polder water penetrate in drinking water, b) assess the lifelong exposure of consumers to pharmaceuticals via drinking water and c) assess the possible individual and mixture health risks associated with this exposure. To fulfill these aims, a 2-year set of 4-weekly monitoring data of pharmaceuticals was used from three drinking water production plants. The 42 pharmaceuticals that were monitored were selected according to their consumption volume, earlier detection, toxicity and representation of the most relevant therapeutic classes. Lifelong exposures were calculated from concentrations and compared with therapeutic doses. Health risks were assessed by benchmarking concentrations with provisional guideline values. Combined risks of mixtures of pharmaceuticals were estimated using the concept of Concentration Addition. The lifelong exposure to pharmaceuticals via drinking water was calculated to be extremely low, i.e. a few mg, in total corresponding to <10% of the dose a patient is administered on one day. The risk of adverse health effects appeared to be negligibly low. Application of Concentration Addition confirmed this for the mixture of pharmaceuticals simultaneously present. The investigated treatment plants appeared to reduce the (already negligible) risk up to 80%. The large available monitoring dataset enabled the performance of a realistic risk assessment. It showed that working with maximum instead of average concentrations may overestimate the risk considerably.Science of The Total Environment 07/2014; 496C:54-62. DOI:10.1016/j.scitotenv.2014.07.022 · 3.16 Impact Factor