Quantifiable risk-benefit assessment of micronutrients: From theory to practice.

The EU Food Supplements Directive (2002/46/EC) mandates the determination of both maximum and minimum permitted levels (MPLs) for micronutrients. In order to determine MPLs which are feasible for particular population groups, a scientific approach should be used in which risk of high intake, risk of inadequacy and benefits are assessed in an integrated way taking all available data and severity and incidence of effect into account. In 2004, Renwick et al. (ILSI Europe) published a scientifically valid, flexible and pragmatic basis for a risk-benefit approach, which has been further developed here to make it a practical and quantifiable approach to be used by risk managers. The applicability of the approach is demonstrated using demo cases on iron and folate. The proposed approach has the capacity to utilize all relevant data available, including data from human studies, bioavailability data showing variability between specific forms of micronutrients and, in the case of animal studies, data on species comparability. The approach is therefore both practical and flexible, making it well suited to risk managers tasked with determining safe intake levels for micronutrients in different forms and for particular population groups.

Relevance of bioaccumulating substances in the TTC concept.

Recently, the European Food Safety Authority (EFSA) stated that the Threshold of Toxicological Concern (TTC) thresholds should not be used for substances that are known or predicted to accumulate. Bioaccumulation of substances is usually considered unfavourable but so far a relation with toxicity at low dose exposure is insufficiently investigated to draw conclusions on the relevance of bioaccumulation at low dose exposure. In this manuscript it is investigated which physical chemical properties are related to bioaccumulation in order to predict accumulating properties of a substance, and is evaluated if the toxicity of known bioaccumulating substances is higher than for non-accumulating substances. Based on the evaluation it is concluded that the current TTC thresholds are derived with a dataset in which bioaccumulating substances are present, whereas the toxicity of the bioaccumulating substances is already taken into account in the TTC thresholds. The authors demonstrated that there is no need to exclude potential bioaccumulating substances from the TTC concept.

A TTC threshold for acute oral exposure to non-genotoxic substances.

To derive an acute TTC threshold, the correlation between Allowable Daily Intakes (ADIs, chronic values) and Acute Reference Doses (ARfDs) of pesticides evaluated in the EU was investigated and their distributions were compared. The correlation between ARfDs and ADIs was significant (p = 0.01), but weak (r(2) = 0.051). Consequently, using this approach to derive acute TTC values does not seem valid. Therefore, the distributions of ARfDs and ADIs were compared directly, in order to extrapolate from chronic to acute TTC values. This comparison made for the combined Cramer structural class II and III pesticides showed a ratio ARfD/ADI of approximately 3 at the fifth percentile of the distributions. Based on these results, it is justified to propose a TTC for acute effects for Cramer III substances by multiplying the Cramer class III TTC threshold of 90 µg/person/day with a factor 3. This leads to an acute TTC threshold based on the Munro dataset for Cramer class III substances of 270 µg/person/day.

Reevaluation of the Munro dataset to derive more specific TTC thresholds.

The threshold of toxicological concern (TTC) concept is a risk assessment tool for substances present at low oral exposure and lacking hazard data. In the past, several thresholds were elaborated by Munro et al. (1996) and Kroes et al. (2004). For these TTC thresholds, the Cramer class III threshold is based on a broad spectrum of substances, including organophosphates. For organophosphates a separate threshold was elaborated by Kroes et al. (2004), however without adjustment of the Cramer class III threshold. Moreover, reference was made by Munro et al. (2008) that for organohalogens a separate threshold also may apply whereas the EFSA (2012) considers that carbamate substances with anti-choline esterase activity can be included in the threshold for organophosphates. In this paper, a reevaluation of the Munro dataset (original TTC database) was performed, focused on the thresholds for organophosphates including carbamates, organohalogens and remaining Cramer class III substances. This way thresholds for each of these groups are elaborated. As a results of the current reevaluation of the Munro dataset, thresholds for life-time exposure are elaborated for the group of organophosphates including carbamates, the group of organohalogens and the remaining Cramer class III substances, being 0.30, 1.5 and 4.0 µg/kg bodyweight/day, respectively.

Complex mixtures: relevance of combined exposure to substances at low dose levels.

Upon analysis of chemically complex food matrices a forest of peaks is likely to be found. Identification of these peaks and concurrent determination of the toxicological relevance upon exposure is very time consuming, expensive and often requires animal studies. Recently, a safety assessment framework based on the Threshold of Toxicological Concern (TTC) was published to assess the safety of chemically complex matrices more efficiently. In this safety assessment framework, the toxicological relevance of exposure to unidentified substances in chemically complex food matrices can be related to the Cramer class III TTC threshold, currently set at 90 µg/day. However, possible additive or synergistic effects of combined exposure is not covered. The current evaluation describes the relevance of combined low dose exposure to unidentified substances in chemically complex food matrices. It is concluded that to some extent cumulative effects at exposure levels for each substance at or below the Cramer class III TTC threshold, being present in a complex mixture including food, might occur. However the health relevance of possible cumulative effects at this dose level is considered to be that low that a need for a correction factor to cover possible cumulative effects is very low to absent.