4B and D), a consistent mechanism would have been expected, resulting in a Nutlin-3a single dose–response curve. Thus, the difference in the slopes of the dose–response relationships for the MWO and LWO exposures suggests different toxicity mechanisms for the same response. Changes in potency generally occur from different modifying factors, as suggested above, whereas changes in slope (toxic mechanism) are generally thought to result from the presence of different toxicants acting by different mechanisms of action. Quantitative

data on such modifying factors that could have contributed to changes in slope, such as the potential of microbial action either directly or through formation of metabolites as a potential cause were not available from this study to definitively address the source of the shift in the mechanism of action. Thus, for sublethal endpoints, a convincing monotonic dose–response relationship was not established linking aqueous TPAH or HMW alkyl-PAH concentrations with observed toxicity. Reduced jaw,% effective swimmers, and pericardial edema,

sublethal responses that were also reported by Carls et al. (1999) for all treatments, also show two dose–response relationships as occurred with larval yolk sac edema and spinal defects (Fig. 4) and show LWO data points with no toxicity at higher TPAH and HMW alkyl-PAH concentrations than MWO points that show a toxic effect. Although PAH are likely contributors to the observed sublethal responses, causation has not been established. Other chemicals in the effluents

probably contributed to lethal and sublethal BIRB 796 molecular weight responses, particularly in the MWO experiment. It is likely that PAH and alkane biodegradation products and microbial metabolites contributed to the toxicity of the column effluents, particularly for the MWO effluents. For example, some oxygenated PAH (microbial degradation products of PAH) are as toxic or more toxic than the metabolized PAH to early life stages of fish and produce sublethal effects, including yolk sac edema and spinal defects, similar to those associated with exposure to complex mixtures of PAH (Carney et al., 2008 and Fallahtafti et al., 2012). These biodegradation products would not be detected in water and tissues by the analytical methods used by Carls et al. (1999). Therefore, aqueous TPAH concentration would not be an accurate dose metric for Alectinib datasheet these experiments if such materials are contributing significantly to the observed responses. An assessment based on tissue residues, assuming that all toxicants were measured, might have led to a better understanding of the relationship between exposure and effects. However, a comparison across all treatments could not be performed because tissue PAH concentration data were not collected from all doses in the LWO study. Fig. 3 of Carls et al. (1999) suggests that the toxicokinetics for PAH in the two studies were substantially different on a wet-tissue-weight basis.