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Comment on "Assessing Aromatic-Hydrocarbon Toxicity to Fish Early Life Stages Using Passive-Dosing Methods and Target-Lipid and Chemical-Activity Models".

R Butler and co-workers reported a comprehensive zebrafish early life stage toxicity study of aromatic hydrocarbons: Passive dosing was applied to tightly control the exposure of several hydrophobic organic chemicals in 30 day chronic toxicity tests, and constant exposure concentrations were carefully confirmed by analytical measurements. The embryo acute toxicity of phenanthrene in this recent study (LC50 of 334 μg/L) agreed very well with another recent shortterm study with the same test organism, passive dosing system and exposure time (LC50 of 310 μg/L ). While experimental results agreed well, the subsequent data analysis and the conclusions drawn were different between the studies. In our passive dosing studies, baseline toxicity initiated typically within the reported chemical activity range for baseline toxicity of 0.01−0.1. We have also observed that several solid compounds with high melting points did not reach sufficient chemical activity for exerting baseline toxicity even at their solubility limit. We explained this by a thermodynamic melting point cutoff in toxicity, and showed that such nontoxic compounds still can contribute to mixture toxicity, because of the solubility additivity for solid chemicals. Two main results highlighted in the TOC Figure in Butler et al. were in conflict with our studies: (1) lethality appeared to require higher chemical activities (chemical activity >0.1) and (2) the distance between LC50 and subcooled liquid solubility appeared to decrease with increasing hydrophobicity, possibly indicating a toxicity cutoff. In order to shed light on this apparent discrepancy between the studies, we replotted the 5 day embryo mortality data (Table 1) from Butler and co-workers against log Kow. Generic regressions for subcooled liquid solubility (SL) served as visual reference for chemical activity of unity, they were published by Mackay et al. (log SL = 3.26−1.00 log Kow; Figure 1A) and Di Toro et al. (log SL = 3.54−1.10 log Kow; Figure 1B). All LC50 values were well within the reported chemical activity range for baseline toxicity in Figure 1A, and a little closer to the upper limit in Figure 1B. The two compounds without acute toxicity had high melting points and a maximum chemical activity near the lower limit of the baseline toxic range. The absence of toxicity was thus consistent with the melting point cutoff in toxicity. We then fitted a linear regression to the LC50 values from Butler et al.: log LC50 = 2.34−1.10 log Kow (slope 95% CI: −1.43 to −0.76, r = 0.95, n = 6). Importantly, the slope was very close to and statistically not significantly different from the slopes of either generic regression for SL, in excellent agreement with an earlier study that included chemicals with higher log Kow values 4 (see Figure 1B in reference 4). The experimental results from Butler et al. do thus neither indicate that LC50 values approach SL nor indicate a hydrophobicity cutoff in toxicity at or near the tested range. Eventually, some of the reasons for the apparent disagreement between the studies were found. Butler and co-workers plotted their data after adjustment by the target lipid model (TLM) rather than plotting actual experimental LC50 values. The TLM adjusted LC50 values were markedly higher than the experimental LC50 values, which partly explains the divergence in the results. Another potential cause for differences is