# “The Dose Makes the Poison”: Relevance of Paracelsus’s Principle for Modern Chemical Hazard Assessment with New Approach Methodologies

## TL;DR

Modern chemical hazard assessments using new methods should consider dose-response relationships and baseline toxicity to avoid misclassifying chemicals as non-toxic.

## Contribution

The paper introduces the concept of 'persistent toxicity' as an integrative hazard metric for chemical substitution and safe-by-design approaches.

## Key findings

- Dichotomizing NAMs results into toxic/nontoxic categories introduces uncertainty in hazard assessment.
- Baseline toxicity predictions can fill data gaps for hard-to-test chemicals.
- Combining persistence and toxicity into a 'persistent toxicity' metric improves hazard evaluation.

## Abstract

New approach methodologies
(NAMs) including in vitro assays and
in silico prediction methods that are based on mechanistic understanding
of the pathways of toxicity have changed how we nowadays assess the
hazard and risk of chemicals in commerce. Quantitative dose–response
relationships obtained from NAMs are often dichotomized into categorical
outcomes (toxic/nontoxic), introducing uncertainty and potential misclassification
in hazard characterization because the applicability domain of NAMs
is currently constrained to the medium-hydrophobicity segment of the
chemical universe. Until physicochemical limitations to the testability
of (super)­hydrophobic chemicals are overcome and hydrophilic and charged
chemicals are tested at higher doses than is present practice, “no
response” should not be equated with an absence of toxicity.
Toxicity is not categoricalit is the dose that makes the poison.
Data gaps for difficult-to-test chemicals can be filled with baseline
toxicity predictions. Baseline toxicity is the minimum toxicity, but
it is often a robust predictor. Persistence constitutes a hazard criterion
in its own right. Combining persistence with toxicity into a “persistent
toxicity” metric may provide a more integrative indicator of
the hazard potential. Persistent toxicity indicators measured with
NAMs could play a pivotal role in comparative hazard assessment for
substitution chemicals and the development of safe and sustainable
by design (SSbD) chemicals.