Threshold of toxicological concern for chemical substances present in the diet: A practical tool for assessing the need for toxicity testing

The de,minimis concept acknowledges a human exposure threshold value for ch emicals below which there is no significant risk to human health. It is the underlying principle for the US Food and Drug Administration (FDA) regulat ion on substances used in food-contact articles. Further to this, the princ iple of Threshold of Toxicological Concern (TTC) has been developed and is now used by the joint FAO/WHO Expert Committee on Food Additives (JECFA) in their evaluations. Establishing an accepted TTC would benefit consumers, i ndustry and regulators, since it would preclude extensive toxicity evaluati ons when Lumen intakes are below such threshold, and direct considerable ti me and cost resources towards testing substances with the highest potential risk to human health. It was questioned, however, whether specific endpoin ts that may potentially give rise to low-dose effects would be covered by s uch threshold. In this review., the possibility of defining a TTC for chemical substances present in the diet was examined for general toxicity endpoints (including carcinogenicity), as well as for specific endpoints, namely neurotoxicity a nd developmental neurotoxicity, immunotoxicity and developmental toxicity. For each of these endpoints, a database of specific no-observed-effect leve ls (NOELs) was compiled by screening oral toxicity studies. The substances recorded in each specific database were selected on the basis of their demo nstrated adverse effects. For the neurotoxicity and developmental neurotoxi city databases, it was intended to cover all classes of compounds reported to hare tither a demonstrated neurotoxic or developmentally neurotoxic effe ct, or at least, on a biochemical or pharmacological basis were considered to have a potential for displaying such effects. For the immunotoxicity end point, it was ensured that only immunotoxicants were included in the databa se by selecting most of the substances from the Luster er al. database, pro vided that they satisfied the criteria for immunotoxicity defined by Luster . For the developmental toxicity database, substances were selected from th e Munro ct nl. database that contained the lowest NOELs retrieved from the literature for more than 600 compounds. After screening these, substances s helving any effect which could point to developmental toxicity as broadly d efined by the US EPA (1986) were recorded in the database. Additionally., endocrine toxicity and allergenicity, were addressed as two separate cases, using different approaches and methodology. The distributions of NOELs for the neurotoxicity, developmental neurotoxici ty and developmental toxicity endpoints were compared with the distribution of NOELs for non-specific carcinogenic endpoints. As the immunotoxicity database was too limited to draw such a distribution of immune NOELs, the immunotoxicity endpoint,vas evaluated by comparing imm une NOELs (or LOELs-lowest-observed-effect levels-when NOELs were not avail able),vith non-immune NOELs (or LOELs), in order to compare the sensitivity of this endpoint with non-specific endpoints. A different methodology was adopted for the evaluation of the endocrine tox icity endpoint since data currently available do not permit the establishme nt of a clear causal link between endocrine active chemicals and adverse ef fects in humans. Therefore, this endpoint was analysed by estimating the hu man exposure to oestrogenic environmental chemicals and evaluating their po tential impact on human health, based on their contribution to the overall exposure, and their estrogenic potency relative to endogenous hormones. The allergenicity endpoint was not analysed as such. It was addressed in a separate section because this issue is not relevant to the overall populati on but rather to subsets of susceptible individuals, and allergic risks are usually controlled by other means (i.e, labelling) than the Threshold of T oxicological Concern approach. However, as several researchers are currentl y examining the existence of a threshold in allergy, the possibility of det ermining threshold doses for food allergens was put into perspective, and t he likelihood for chemical substances to induce allergy at dietary relevant doses was discussed. The analysis indicated that, within the limitation of the databases, develo pmental neurotoxicity and developmental toxicity were not more sensitive th an other non-specific endpoints. Although the cumulative distribution of NOELs for neurotoxic compounds was significantly loner than those for other non-cancer endpoints, these substa nces were accommodated within the TTC of 1.5 mu g/person/day. Furthermore, the analysis demonstrated that none of the specific non-cancer endpoints ev aluated in the present study was more sensitive than cancer and, that a TTC of 1.5 mu g/person/day based on cancer endpoints provides an adequate marg in of safety. Analysis of the immunotoxicity database should that for the group of immuno toxicants examined here, the specific immunotoxic endpoint was not more sen sitive than other endpoints. In other words, the distribution of immunotoxi c NOELs for these compounds did not appear to differ from the distribution of nonspecific endpoints NOELs for the same compounds. The dietary intakes of environmental oestrogenic chemicals were estimated a nd their oestrogenic potencies were compared with that of endogenous hormon es, in order to assess their impact on human health. The results are in lin e with scientific data obtained so far, suggesting that estrogenic compound s of anthropogenic origin, in comparison with endogenous hormones, possess only little hormonal activity lilts phytoestrogens. Results of animal studi es do not suggest that hormonal effects are to be expected from the rather lon concentrations found in foods. More data are necessary to determine threshold doses for food allergens. Ho wever, provided that numerous criteria need to be satisfied before sensitiz ation occurs, it is unlikely that small molecules used in little amounts in foods would induce such reactions. On the basis of the present analysis, which was conducted using conservativ e assumptions at each step of the procedure (i.e. in data compilation and d ata analysis), and continually adopting a "worst case" perspective, it can be concluded that a Threshold of Toxicological Concern of 1.5 mu g/person/d ay provides adequate safety assurance. Chemical substances present in the d iet that are consumed at levels below this threshold pose no appreciable ri sk. Moreover, for compounds which do not possess structural alerts for genotoxi city and carcinogenicity, further analysis mag indicate that a higher Thres hold of Toxicological Concern mag he appropriate. (C) 2000 Elsevier in Scie nce Ltd. All rights reserved.