Critical analysis of literature on low-dose synergy for use in screening chemical mixtures for risk assessment

Imperial College London, London, UK.
Critical Reviews in Toxicology (Impact Factor: 5.1). 02/2011; 41(5):369-83. DOI: 10.3109/10408444.2010.543655
Source: PubMed

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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    • "In addition, when doses are around the NOAEL, there are minor deviations from the dose additivity hypothesis, as shown by the data reported in Tables 2 and 3 where different approaches to combined exposure have been taken. In both the fixed ratio approach (Table 2) and the approach of Table 3 where the concentration of one compound was kept fixed while those of the other compound were increased, the deviation from the additivity hypothesis was not significant, as pointed out in other cases (Boobis et al., 2011; ECETOC, 2012). A limited number of in vivo confirmatory studies were performed. "
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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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    • "The need to consider multiple exposures simultaneously presents a difficult methodological problem (Boobis et al., 2011). On the one hand, it is possible that certain exposures act together, or perhaps interact, in ways that may influence health outcomes (Johns et al., 2012; Sexton, 2012). "
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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 · 0.77 Impact Factor
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    • "In addition to chemical structure and mode of action, target organ and mechanism of action should be taken into account in assessing the possible additive (or synergistic) effects of contaminants (Boobis et al., 2011). Rennen et al. (2011) recently developed a system of assessing chemically complex food matrices based on the decision scheme of Kroes et al. and used new thresholds derived from new analyses of the original databases. "
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    ABSTRACT: Threshold of Toxicological Concern (TTC) decision-support methods present a pragmatic approach to using data from well-characterized chemicals and protective estimates of exposure in a stepwise fashion to inform decisions regarding low-level exposures to chemicals for which few data exist. It is based on structural and functional categorizations of chemicals derived from decades of animal testing with a wide variety of chemicals. Expertise is required to use the TTC methods, and there are situations in which its use is clearly inappropriate or not currently supported. To facilitate proper use of the TTC, this paper describes issues to be considered by risk managers when faced with the situation of an unexpected substance in food. Case studies are provided to illustrate the implementation of these considerations, demonstrating the steps taken in deciding whether it would be appropriate to apply the TTC approach in each case. By appropriately applying the methods, employing the appropriate scientific expertise, and combining use with the conservative assumptions embedded within the derivation of the thresholds, the TTC can realize its potential to protect public health and to contribute to efficient use of resources in food safety risk management.
    Critical reviews in food science and nutrition 10/2013; 53(12):1239-1249. DOI:10.1080/10408398.2012.752341 · 5.18 Impact Factor
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