Linear low-dose extrapolation for noncancer health effects is the exception, not the rule

Abstract

The nature of the exposure-response relationship has a profound influence on risk analyses. Several arguments have been proffered as to why all exposure-response relationships for both cancer and noncarcinogenic end-points should be assumed to be linear at low doses. We focused on three arguments that have been put forth for noncarcinogens. First, the general “additivity-to-background” argument proposes that if an agent enhances an already existing disease-causing process, then even small exposures increase disease incidence in a linear manner. This only holds if it is related to a specific mode of action that has nonuniversal properties—properties that would not be expected for most noncancer effects. Second, the “heterogeneity in the population” argument states that variations in sensitivity among members ofthe target population tend to “flatten out and linearize” the exposure-response curve, but this actually only tends to broaden, not linearize, the dose-response relationship. Third, it has been argued that a review of epidemiological evidence shows linear or no-threshold effects at low exposures in humans, despite nonlinear exposure-response in the experimental dose range in animal testing for similar endpoints. It is more likely that this is attributable to exposure measurement error rather than a true non-threshold association. Assuming that every chemical is toxic at high exposures and linear at low exposures does not comport to modern-day scientific knowledge of biology. There is no compelling evidence-based justification for a general low-exposure linearity; rather, case-specific mechanistic arguments are needed.

Investigation of the state of the art on identification of appropriate reference points for the derivation of health‐based guidance values (ADI, AOEL and AAOEL) for pesticides and on the derivation of uncertainty factors to be used in human risk assessment

“…It is now well accepted that the presence or absence of a mathematical or absolute threshold cannot be proven or disproven experimentally as this would require an infinitely sensitive method with an infinitely large number of animals and an infinitely small dose, down to one molecule (Slob, 1999;Crump, 2011;Rhomberg et al, 2011). Science is not capable of determining the shape of the dose response at very low doses.…”

Thresholds of Toxicological Concern – Setting a threshold for testing below which there is little concern

“…The soundness of this recommendation has been questioned (Rhomberg et al, 2011;Bogen, 2016). (Rhomberg et al, 2011). What Lorenz Rhomberg and colleagues are voicing here is the consequence of giving up the safe dose concept, which would annihilate a lot of the risk assessment currently done and also severely impair the TTC concept.…”

“…The soundness of this recommendation has been questioned (Rhomberg et al, 2011;Bogen, 2016). (Rhomberg et al, 2011).…”

European Union’s strategy on endocrine disrupting chemicals and the current position of Slovenia

“…Depending on the quantity and the quality of available data, either the threshold (42,51,54) or the non-threshold (36, 59) approach should be used. Slovenia also favours the use of semiquantitative decision trees for regulatory purposes.…”