Abstract
The maximal chemical concentration that causes an acceptably small or no effect in an organism or isolated cells is an often-sought-after value in toxicology. Existing approaches to derive this value have raised several concerns; thus, it is often chosen case-by-case based on personal experience. To overcome this ambiguity, we propose an approach for choosing the non-toxic concentration (NtC) of a chemical in a rational, tractable way. We developed an algorithm that identifies the highest chemical concentration that causes no more than 10% effect (≤ EC10) including the modeled 95% confidence intervals and considering each of the measured biological replicates; and whose toxicity is not significantly different from no effect. The developed algorithm was validated in two steps: by comparing its results with measured and modeled data for 91 dose-response experiments with fish cell lines and/or zebrafish embryos; and by measuring actual effects caused by NtCs in a separate set of experiments using a fish cell line and zebrafish embryos. The algorithm provided an NtC that is more protective than NOEC (no-observed-effect-concentration), NEC (modeled no-effect concentration), EC10 and BMD (benchmark dose). Despite focusing on small-scale bioassays here, this study indicates that the NtC algorithm could be used in various systems. Its application to the survival of zebrafish embryos and to metabolic activity in cell lines showed that NtCs can be applied to different effect measure­ments, time points, and levels of biological organization. The algorithm is available as Matlab and R source code, and as a free, user-friendly online application.
Highlights
1.1 Non-toxic concentrations in ecotoxicology Selecting the maximum chemical concentration that causes an acceptably small or no toxic effect in a test object, such as an organism or isolated cells, is often required or recommended for environmental toxicology purposes (OECD, 2006; US EPA, 1991; Shao, 2000)
non-toxic concentration (NtC) algorithm assumptions The algorithm for the determination of the highest chemical concentration that is not yet toxic (NtC) was developed based on the following assumptions: i) a dose-response curve can be fitted to measured data and confidence intervals can be determined, ii) NtC does not cause an effect significantly different from the control (“NtCupperCI”), iii) the effect of NtC does not exceed EC10 (“NtClowerCI”), iv) tested concentrations lower than NtC do not cause effects greater than 10% (“NtCmeasured”)
The purpose of this study was to develop an algorithm for choosing the non-toxic concentration of a chemical in a rational, tractable way, so that it does not depend on subjective experience
Summary
1.1 Non-toxic concentrations in ecotoxicology Selecting the maximum chemical concentration that causes an acceptably small or no toxic effect in a test object, such as an organism or isolated cells, is often required or recommended for environmental toxicology purposes (OECD, 2006; US EPA, 1991; Shao, 2000). In order to avoid having to pre-set a concrete ECx or BMR, several threshold models have been introduced (Cox, 1987; Kooijman, 1996; Kooijman and Bedaux, 1996; Pires et al, 2002) that can be used to determine the so called “no effect concentration” (NEC), i.e., the highest modeled parametric concentration that does not cause an effect These models may, not fit the measured data very well and they are often criticized due to their marginalization of hormesis (Calabrese, 2007, 2009). Jager (2011) argued that, because toxicity is the response of a dynamic biological system, a simplified representation of reality should be created, e.g., Received January 23, 2017; Accepted June 20, 2017; Epub June 26, 2017; doi:10.14573/altex.1701231
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