An Approach to Characterizing the Type of Combined Environmental Toxicity Based on Epidemiologically Assessed Exposure-Response Relationships

Abstract

Using a dataset obtained in an earlier published epidemiological study that revealed the dependence of the probability of subclinical kidney damage in 260 children on the concentration of lead and cadmium in their urine, we have tested some methodological approaches to assessing the type of combined nephrotoxicity produced by these two metals. We have found that the environmentally caused damage to kidneys in children from lead and cadmium is less than additive (manifestation of toxicological antagonism).Given the subadditivity (antagonism) of the damaging effect of lead and cadmium on kidneys as demonstrated on the basis of epidemiological data, we believe that the summation of corresponding risks is a sufficiently conservative principle creating an additional margin of safety and limiting the uncertainty of risk assessment on the whole.Of theoretical interest is the demonstrated consistency of this assessment of the type of combined toxicity irrespective of whether it is carried out on the basis of the paradigm of effect additivity or dose additivity. This enables us to speak in favor of considering the so-called Bliss independence and Loewe additivity as complementary simplified models of the same fairly complex process rather than essentially different biological phenomena. The example studied suggests that approaches to the analysis of epidemiological data for the purpose of assessing combined risk should be tested using each of these models rather than restricting it to one of them based on an a priori choice.

Toxicity of exposure to binary mixtures of four anti-neoplastic drugs in Daphnia magna and Ceriodaphnia dubia

“…The similar toxicological sensitivities of D. magna and C. dubia, already demonstrated in previous studies (Constantine and Huggett, 2010;Parrella et al, 2014) were confirmed also in the present study, in fact most of mixtures showed a Bliss independence interaction in both organisms. Each cytostatic, when in mixture, likely exerted effects on non-target organisms at concentrations not depending on the other cytostatic (Katsnelson et al, 2011). This interaction, also known as heteroadditivity, was Two independent experiments were performed on 10 organisms for each test solution to obtain the specific effect percentage.…”

“…Although the concentrations of these drugs in aquatic systems are very low, chronic exposures of organisms may be of environmental concern, especially when they occur as mixtures (Brezovšek et al, 2014). Compounds with the same mode and biological site of action will act in mixtures according to the model of Concentration Addition (CA, Loewe additivity) while substances with independent mechanism and/or different biological sites could act in mixture according to the model of Independent Action (IA, Bliss independence) (Katsnelson et al, 2011). As most of anticancer drugs interfere with DNA, acting on the same biological target but often with different modes of action, it is difficult to predict their interaction in mixtures.…”

Experimental study and mathematical modeling of toxic metals combined action as a scientific foundation for occupational and environmental health risk assessment. A summary of results obtained by the Ekaterinburg research team (Russia)

“…The exact meaning of each of these terms can, however, vary broadly depending on which paradigm of combined adverse action is meant, even if not explicitly, by a researcher ( e.g. [5] , [28] , [9] , [10] , [8] or, by an Agency ( e.g. the US EPA or the ACGIH).…”

“…Moreover, the type of combined toxicity may essentially differ depending on which of the components prevails in the combination quantitatively. In particular, this dependence gives biphasic Loewe isoboles, an example of which (for combined LD50 of sodium fluoride and manganese chloride in both mice and rats) was presented in Katsnelson [9] and Katsnelson et al [10] . In this case, the combination proved subadditive where fluoride prevailed but superadditive where manganese did.…”

Prediction and assessment of ecogenotoxicity of antineoplastic drugs in binary mixtures

“…Compounds with the same mode and biological site of action could act in mixture according to the CA model (Loewe additivity or isoadditivity); compounds with different mechanisms and/or different biological sites of action cannot be considered as dilutions of each other and may rather act in mixture according to the IA model (Bliss independence or heteroadditivity) (Katsnelson et al 2011). Some recent studies concerning the effects of anticancer drugs in mixtures suggest that combinations might follow or deviate from expectations based on these reference models (Ermler et al 2014;Mater et al 2014).…”