Toward a Universal Acute Fish Threshold of Toxicological Concern

Abstract

Threshold of toxicological concern (TTC) is a concept that has been around for decades in human health sciences. Ecotoxicology recently adopted a variant of this concept as eco-TTC. Adoption of the concept of TTC considerably reduces the amount of animal testing required for regulatory purposes. We provide an application of a universal TTC for the entirety of acute fish toxicity data (i.e., establishment of an exposure level below which there would be minimal probability of acute fish toxicity for any chemical, without consideration of mechanism of action). We calculated TTC values for a number of subgroups using various approaches. These approaches were evaluated using data from a cohort of 69 999 acute fish toxicological assays. This database was normalized/curated for units, exposure duration, quality assurance/control, and duplicates, which reduced it to 47 694 assays. Data were not normally but log-normally distributed, making geometric means the most appropriate statistical parameter. Thus, we developed descriptive statistics using geometric means with 95, 99, and 99.9% confidence intervals. Various assessment factors (akin to predicted-no-effect concentration derivation) were applied to the geometric means to derive TTCs. Other approaches employed were the calculation of y = 0 intercepts as well as development of 95 and 99.75% cutoffs of cumulative data as well as modular uncertainty scoring tool (MUST) analysis. All of the methodologies derived highly congruent TTCs ranging from to 2 to 8 μg/L except for the 99.75th percentile cutoff of 0.3 μg/L. The data would be most useful in making a binary testing/no testing required decision. For acute fish toxicity, a TTC value of 2 μg/L was most appropriate, based on the 95th percentile of data distribution without any assessment factor.

Reply to Comment on Plugge et al. 2021 “Toward a Universal Acute Fish Threshold of Toxicological Concern”

“…Detailed quality control of every study imaginable is not possible-screening is the only option. As we acknowledged in our study (Plugge et al 2021), derivation of say a water quality criterion…”

“…In addition, the context of toxicological assessments matters, and because context varies and assessments are carried out addressing different needs (often in different parts of the chemical space), we prefer to view contrasting approaches as complementary rather than competitive, so long as applicability and underlying limitations are clearly defined. We invite the authors to scrutinize our publication record to find that some of our past efforts would appear to be "ideologically" orthogonal to the study being discussed in their letter (Plugge et al 2021); yet, we do not perceive this as a conflict with some agreed-on central dogma. It is horses for courses, and although the approach presented may appear crude, its utility cannot be denied in the context of real-world data.A threshold of toxicological concern (TTC) is a screening tool used to assess the risk for a chemical of unknown toxicity and has been around for nearly half a century.…”

“…First, the TTC as presented is a TTC (specifically not an eco-TTC) and was calculated without any adjustment factor, as described in detail in the study (Plugge et al 2021). The derived TTC is based solely on a 95% distribution of acute fish toxicity (a figure of 99.75% of data is also provided).…”

Comment on Plugge et al. 2021 “Toward a Universal Acute Fish Threshold of Toxicological Concern”

“…After an examination of the data set used for the Plugge et al (2021) calculations (provided as their Supplemental Data), the following findings were made. 1) The original data set was 47 694 records for 6133 unique substances.…”

“…If proper and appropriate handling of metals data was not possible (e.g., normalizing to a set hardness value for the purpose of aggregating metals data in distributions), the authors should have excluded metals from this analysis. Although we have not re-analyzed the Plugge et al (2021) data set with this in mind, we expect that a grouping structure based on the dissociated metal ion driving toxicity would result in a significant portion of the data being collapsed together and thus alter the CTD 0.05 distribution.…”