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

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.