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.
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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; 79. DOI:10.1016/j.fct.2014.07.006 · 2.90 Impact Factor
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ABSTRACT: Atrazine (ATR) is a commonly used agricultural herbicide that has been the subject of epidemiologic studies assessing its relation to reproductive health problems. This review evaluates both the consistency and the quality of epidemiologic evidence testing the hypothesis that ATR exposure, at usually encountered levels, is a risk factor for birth defects, small for gestational age birth weight, prematurity, miscarriages, and problems of fetal growth and development. We followed the current methodological guidelines for systematic reviews by using two independent researchers to identify, retrieve, and evaluate the relevant epidemiologic literature on the relation of ATR to various adverse outcomes of birth and pregnancy. Each eligible paper was summarized with respect to its methods and results with particular attention to study design and exposure assessment, which have been cited as the main areas of weakness in ATR research. As a quantitative meta-analysis was not feasible, the study results were categorized qualitatively as positive, null, or mixed. The literature on ATR and pregnancy-related health outcomes is growing rapidly, but the quality of the data is poor with most papers using aggregate rather than individual-level information. Without good quality data, the results are difficult to assess; however, it is worth noting that none of the outcome categories demonstrated consistent positive associations across studies. Considering the poor quality of the data and the lack of robust findings across studies, conclusions about a causal link between ATR and adverse pregnancy outcomes are not warranted.Birth Defects Research Part B Developmental and Reproductive Toxicology 06/2014; 101(3). DOI:10.1002/bdrb.21101 · 1.17 Impact Factor
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ABSTRACT: The identification of the major associations of pesticides to which the population is exposed is the first step for the risk assessment of mixtures. Moreover, the interpretation of the mixtures through the individuals' diet and the characterization of potentially high-risk populations constitute a useful tool for risk management. This paper proposes a method based on Non-Negative Matrix Factorization which allows the identification of the major mixtures to which the French population is exposed and the connection between this exposure and the diet. Exposure data of the French population are provided by the Second French Total Diet Study. The NMF is implemented on consumption data to extract consumption systems which are combined with the residue levels to link dietary behavior with exposure to mixtures of pesticides. A clustering of the individuals is achieved in order to highlight clusters of individuals with similar exposure to pesticides/consumption habits. The model provides 6 main consumption systems, 6 associated mixtures of pesticides and the description of the population which is most exposed to each mixture. Two different ways to estimate the matrix providing the mixtures of pesticides to which the population is exposed are suggested. Their advantages in different contexts of risk assessment are discussed.Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 06/2013; 59. DOI:10.1016/j.fct.2013.06.006 · 2.61 Impact Factor