Critical analysis of literature on low-dose synergy for use in screening chemical mixtures for risk assessment
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.
Available from: Johnathan Furr
- "We also evaluated additional response levels (e.g., ED5, ED10, ED 20, ED25, ED75 and ED90), so that if clear deviation of observed data from modeled data were detected using the forcefit approach, the dose dependency of the deviation could be evaluated to observe whether there were dose-dependent interactions of the observed data to the mixture models. Furthermore, for the postnatal endpoints not accurately predicted by DA (DA ref or DA all ) or RA in the forcefit analysis, we calculated the magnitude of interaction for the observed data relative to the mixture model predictions (Boobis et al., 2011). For example, a magnitude of interaction of 2.0 would be calculated if the observed ED20 of the mixture is 20 and the mixture model predicted ED20 based on additivity is 40. "
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ABSTRACT: Challenges in cumulative risk assessment of anti-androgenic phthalate mixtures include a lack of data on all the individual phthalates and difficulty determining the biological relevance of reduction in fetal testosterone (T) on postnatal development. The objectives of the current study were 2-fold: (1) to test whether a mixture model of dose addition based on the fetal T production data of individual phthalates would predict the effects of a 5 phthalate mixture on androgen-sensitive postnatal male reproductive tract development, and (2) to determine the biological relevance of the reductions in fetal T to induce abnormal postnatal reproductive tract development using data from the mixture study. We administered a dose range of the mixture (60, 40, 20, 10 and 5% of the top dose used in the previous fetal T production study consisting of 300 mg/kg per chemical of benzyl butyl (BBP), di(n)butyl (DBP), diethyl hexyl phthalate (DEHP), di-isobutyl phthalate (DiBP) and 100 mg dipentyl (DPP) phthalate/kg; the individual phthalates were present in equipotent doses based on their ability to reduce fetal T production) via gavage to Sprague Dawley rat dams on GD8-postnatal day 3. We compared observed mixture responses to predictions of dose addition based on the previously published potencies of the individual phthalates to reduce fetal T production relative to a reference chemical and published postnatal data for the reference chemical (called DA ref). In addition, we predicted DA (called DA all) and response addition (RA) based on logistic regression analysis of all 5 individual phthalates when complete data were available. . DA ref and DA all accurately predicted the observed mixture effect for 11of 14 endpoints. Furthermore, reproductive tract malformations were seen in 17% to 100% of F1 males when fetal T production was reduced by about 25% to 72%, respectively.
- "Current frameworks of risk assessments deal in most cases with a single chemical, but at the same time, as there are multiple chemicals used together, there are concerns regarding the cumulative or combined effects of chemical mixtures (Berenbaum, 1977; Feron et al., 1995; Teuschler and Hertzberg, 1995; Groten et al., 2001; Feron and Groten, 2002; McCarty and Borgert, 2006; Boobis et al., 2011; Meek et al., 2011; Cedergreen, 2014). In particular, for pesticides or biocides, risk assessments for combined effects have been conducted, and guidelines or documents for combined effects have also been published by governmental and international organizations (USEPA, 2002, 2003; Kortenkamp et al., 2009; OECD, 2011; European Commission , 2012). "
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ABSTRACT: Many models have been developed to predict the combined effect of drugs and chemicals. Most models are classified into two additive models: independent action (IA) and concentration addition (CA). It is generally considered if the modes of action of chemicals are similar then the combined effect obeys CA; however, many empirical studies report nonlinear effects deviating from the predictions by CA. Such deviations are termed synergism and antagonism. Synergism, which leads to a stronger toxicity, requires more careful management, and hence it is important to understand how and which combinations of chemicals lead to synergism. In this paper, three types of chemical reactions are mathematically modeled and the cause of the nonlinear effects among chemicals with similar modes of action was investigated. Our results show that combined effects obey CA only when the modes of action are exactly the same. Contrary to existing knowledge, combined effects are generally nonlinear even if the modes of action of the chemicals are similar. Our results further show that the nonlinear effects vanish out when the chemical concentrations are low, suggesting that the current management procedure of assuming CA is rarely inappropriate because environmental concentrations of chemicals are generally low.
Copyright © 2015. Published by Elsevier Ireland Ltd.
Available from: Erminio Giavini
- "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.
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