1. General Objective of the Document
In this article, the objective is to explain how to identify, evaluate, and select Toxicological Reference Values (TRVs) used to assess health risks associated with human exposure to chemical substances.
A Toxicological Reference Value is a toxicological indicator used to establish a relationship between exposure to a chemical substance and the potential occurrence of adverse health effects. The document addresses a fundamental question: when several scientific organizations propose different TRVs for the same substance, how can the most scientifically relevant value be selected?
INERIS emphasizes critical evaluation of study quality, toxicological effects, and calculation methods rather than automatically selecting the lowest numerical value.
2. The Two Main Categories of TRVs
| Threshold TRVs | Non-threshold TRVs |
|---|---|
| An exposure level is considered unlikely to cause appreciable adverse health effects. | An adverse effect may theoretically occur even at very low exposure levels. |
| Mainly applicable to systemic toxicity, reproductive effects, and certain non-genotoxic carcinogenic effects. | Mainly applicable to genotoxic carcinogenic effects. |
| Expressed as a reference dose or reference concentration. | Expressed as a unit excess risk (UER). |
TRVs are also classified according to exposure route (oral, inhalation, and occasionally dermal) and duration (acute, subchronic, or chronic). A single chemical substance may exhibit both threshold and non-threshold effects, depending on the mechanisms involved.
3. The Three Stages of the INERIS Methodology
Stage 1 – Identification of Existing TRVs: identify available reference values from scientific organizations.
Stage 2 – Scientific Evaluation of TRVs: evaluate studies, critical effects, dose-response relationships, and uncertainties.
Stage 3 – Selection and Qualification of the Most Relevant TRV: select the most appropriate value and assess confidence in its reliability.
Stage 1 – Identification of Existing TRVs
The first stage identifies available TRVs for a substance, considering exposure route, duration, and type of toxicological effect. INERIS gives priority to values established through independent, collective, and transparent scientific assessment.
The main organizations mentioned include ANSES, US EPA, WHO, ATSDR, OEHHA, RIVM, Health Canada, EFSA, and ECHA. The guide distinguishes genuine TRVs from guideline or regulatory values, which may also incorporate risk-management considerations.
Stage 2 – Scientific Evaluation of TRV Derivation
A. Assessment of Study Quality
Epidemiological and experimental studies are evaluated using study design, characteristics of studied populations or animals, exposure conditions, measured effects, dose-response relationships, statistical analyses, potential biases, and confounding factors. For experimental studies, the guide refers to the Klimisch reliability criteria.
B. Identification of the Critical Effect
The critical effect selected as the basis for deriving a TRV must be relevant to human health, sufficiently documented, and consistent with the overall toxicological profile. The guide pays particular attention to carcinogenic mechanisms, especially genotoxicity.
C. Evaluation of the Critical Dose
NOAEL (No Observed Adverse Effect Level): highest tested dose at which no adverse effect is observed.
LOAEL (Lowest Observed Adverse Effect Level): lowest tested dose at which an adverse effect is observed.
BMD/BMDL (Benchmark Dose/Benchmark Dose Lower Confidence Limit): dose estimated through dose-response modeling and the lower confidence limit associated with that estimate.
Selection depends on the quality of the available data and the scientific validity of the method.
D. Application of Uncertainty Factors
For threshold TRVs, uncertainty factors account for scientific limitations and variability:
| Factor | Uncertainty addressed |
|---|---|
| UFA | Extrapolation from animals to humans (interspecies variability) |
| UFH | Variability within the human population (intraspecies variability) |
| UFS | Extrapolation between exposure durations |
| UFL | Use of a LOAEL instead of a NOAEL |
| Additional factors | Potential limitations or deficiencies in the toxicological database |
These factors should not be applied mechanically without scientific justification. For non-threshold effects, the methodology relies on dose-response modeling and low-dose extrapolation to determine unit excess risk.
Stage 3 – Selection and Qualification of the Most Relevant TRV
INERIS compares available TRVs using the robustness of the key study, relevance of the critical effect, consistency of toxicological reasoning, and justification of extrapolation methods and uncertainty factors. The scientific reasons supporting the selected value must be clearly documented.
No TRV should be selected when the evidence is insufficient to justify the choice. The methodology also includes a qualitative assessment of confidence in the selected value.
4. Practical Relevance for Plant Protection Product Risk Assessment
The methodology is useful for evaluating toxicological data relating to active substances used in plant protection products. It provides a framework for assessing study reliability, critical doses, uncertainty factors, and reference values from different authorities.
However, this guide primarily concerns the selection of TRVs for human health risk assessment. It is not, by itself, a complete regulatory risk assessment methodology for plant protection products.
5. Key Scientific Principles and Conclusions
Table 12 (report pages 48–49) indicates that INERIS generally favors high-quality studies, relevant human data, benchmark dose approaches, and transparent, justified methods. Table 13 (page 51) defines a confidence index from Level 1 (highest) to Level 3 (lowest), including intermediate categories 2a and 2b.
The guide recommends checking for newly established TRVs before using previously selected values.
Overall Conclusion
The relevance of a Toxicological Reference Value depends primarily on the quality of the underlying scientific evidence and the robustness of its derivation methodology, rather than solely on its numerical magnitude.
INERIS proposes a structured, transparent, and scientifically justified approach to selecting TRVs while explicitly considering uncertainty and limitations in toxicological evidence.
This document was published in December 2016. Although it remains a useful methodological reference, current TRVs and scientific recommendations should be verified before regulatory application in 2026.
References
INERIS — Choix de valeurs toxicologiques de référence (VTR) : méthodologie appliquée par l’INERIS. DRC-16-156196-11306A, décembre 2016.
Check updated INERIS values and resources
