Time to revisit the Paracelsus principle of “the dose makes the poison”

Environmental risk assessment approaches used by regulatory agencies around the world were developed on the basis of a methodology published by the National Academy of Sciences. For the hazard characterization step, it is generally accepted that once detectable, a response of an organism to a toxicant increases proportionally with the level of exposure until reaching an upper-limit or maximal-effect level (Emax) beyond which increasing toxicant dose will not increase the response (known as a monotonic dose-response). To assess the dose-response relationship of a chemical, several doses are typically tested to define the no observed adverse effect level (NOAEL) and/or the lowest observed adverse effect level (LOAEL). The NOAEL is considered a conservative default threshold below which a chemical is not expected to induce adverse effects, irrespective of the dose.

Non-monotonic dose-response (NMDR) relationships are more frequently reported today in experimental studies than they were 10 years ago. The endocrine disrupting chemicals (EDCs) are regularly associated with NMDR relationships. Until recently, NMDR relationships were not considered plausible, and thus they were not published, reported, or interpreted as relevant biological phenomena. An increasing number of scientists think that NMDR relationships represent a toxicological reality, but supplementary effort is required to revisit the Paracelsus principle of “the dose makes the poison”.

The assumption that a threshold, or “safe” exposure level exists for chemicals except for carcinogens may be invalid. There are examples of non-carcinogens without an apparent threshold (neonicotinoids, dioxin, dieldrin, endocrine disruptors, and sulfhydryl-reactive metals). It is also clear by now that the threshold model for non-carcinogens may seriously underestimate actual risk. Risk assessments can no longer assume thresholds for non-carcinogens when the shape of the dose-response curve is linear at low concentrations. Risk management of such chemicals should be based on the ALARA principle (“as low as reasonably achievable”).

Citations:
Tennekes HA (2016) A Critical Appraisal of the Threshold of Toxicity Model for Non-Carcinogens. J Environ Anal Toxicol 6:408. doi: 10.4172/2161- 0525.1000408
Lagarde F, Beausoleil C, Belcher SM et al (2015) Non-monotonic dose-response relationships and endocrine disruptors: a qualitative method of assessment. Environ Health. 14: 13. doi: 10.1186/1476-069X-14-13