The de,minimis concept acknowledges a human exposure threshold value for chemicals below which there is no significant risk to human health. It is the underlying principle for the US Food and Drug Administration (FDA) regulation on substances used in food-contact articles. Further to this, the principle 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, industry and regulators, since it would preclude extensive toxicity evaluations when Lumen intakes are below such threshold, and direct considerable time and cost resources towards testing substances with the highest potential risk to human health. It was questioned, however, whether specific endpoints that may potentially give rise to low-dose effects would be covered by such 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 and developmental neurotoxicity, immunotoxicity and developmental toxicity. For each of these endpoints, a database of specific no-observed-effect levels (NOELs) was compiled by screening oral toxicity studies. The substances recorded in each specific database were selected on the basis of their demonstrated adverse effects. For the neurotoxicity and developmental neurotoxicity databases, it was intended to cover all classes of compounds reported to hare tither a demonstrated neurotoxic or developmentally neurotoxic effect, or at least, on a biochemical or pharmacological basis were considered to have a potential for displaying such effects. For the immunotoxicity endpoint, it was ensured that only immunotoxicants were included in the database by selecting most of the substances from the Luster er al. database, provided that they satisfied the criteria for immunotoxicity defined by Luster. For the developmental toxicity database, substances were selected from the Munro ct nl. database that contained the lowest NOELs retrieved from the literature for more than 600 compounds. After screening these, substances shelving any effect which could point to developmental toxicity as broadly defined 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 neurotoxicity 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 immune NOELs (or LOELs-lowest-observed-effect levels-when NOELs were not available),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 toxicity endpoint since data currently available do not permit the establishment of a clear causal link between endocrine active chemicals and adverse effects in humans. Therefore, this endpoint was analysed by estimating the human exposure to oestrogenic environmental chemicals and evaluating their potential 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 population but rather to subsets of susceptible individuals, and allergic risks are usually controlled by other means (i.e, labelling) than the Threshold of Toxicological Concern approach. However, as several researchers are currently examining the existence of a threshold in allergy, the possibility of determining threshold doses for food allergens was put into perspective, and the likelihood for chemical substances to induce allergy at dietary relevant doses was discussed. The analysis indicated that, within the limitation of the databases, developmental neurotoxicity and developmental toxicity were not more sensitive than other non-specific endpoints. Although the cumulative distribution of NOELs for neurotoxic compounds was significantly loner than those for other non-cancer endpoints, these substances were accommodated within the TTC of 1.5 mu g/person/day. Furthermore, the analysis demonstrated that none of the specific non-cancer endpoints evaluated 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 margin of safety. Analysis of the immunotoxicity database should that for the group of immunotoxicants examined here, the specific immunotoxic endpoint was not more sensitive than other endpoints. In other words, the distribution of immunotoxic 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 and their oestrogenic potencies were compared with that of endogenous hormones, in order to assess their impact on human health. The results are in line with scientific data obtained so far, suggesting that estrogenic compounds of anthropogenic origin, in comparison with endogenous hormones, possess only little hormonal activity lilts phytoestrogens. Results of animal studies 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. However, provided that numerous criteria need to be satisfied before sensitization 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 conservative assumptions at each step of the procedure (i.e. in data compilation and data analysis), and continually adopting a "worst case" perspective, it can be concluded that a Threshold of Toxicological Concern of 1.5 mu g/person/day provides adequate safety assurance. Chemical substances present in the diet that are consumed at levels below this threshold pose no appreciable risk. Moreover, for compounds which do not possess structural alerts for genotoxicity and carcinogenicity, further analysis mag indicate that a higher Threshold of Toxicological Concern mag he appropriate.

Threshold of toxicological concern for chemical substances present in the diet: a practical tool for assessing the need for toxicity testing / R. Kroes, C.L. Galli, I. Munro, B. Schilter, L. Tran, R. Walker, G. Wurtzen. - In: FOOD AND CHEMICAL TOXICOLOGY. - ISSN 0278-6915. - 38:2-3(2000), pp. 255-312.

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

C.L. Galli;
2000

Abstract

The de,minimis concept acknowledges a human exposure threshold value for chemicals below which there is no significant risk to human health. It is the underlying principle for the US Food and Drug Administration (FDA) regulation on substances used in food-contact articles. Further to this, the principle 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, industry and regulators, since it would preclude extensive toxicity evaluations when Lumen intakes are below such threshold, and direct considerable time and cost resources towards testing substances with the highest potential risk to human health. It was questioned, however, whether specific endpoints that may potentially give rise to low-dose effects would be covered by such 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 and developmental neurotoxicity, immunotoxicity and developmental toxicity. For each of these endpoints, a database of specific no-observed-effect levels (NOELs) was compiled by screening oral toxicity studies. The substances recorded in each specific database were selected on the basis of their demonstrated adverse effects. For the neurotoxicity and developmental neurotoxicity databases, it was intended to cover all classes of compounds reported to hare tither a demonstrated neurotoxic or developmentally neurotoxic effect, or at least, on a biochemical or pharmacological basis were considered to have a potential for displaying such effects. For the immunotoxicity endpoint, it was ensured that only immunotoxicants were included in the database by selecting most of the substances from the Luster er al. database, provided that they satisfied the criteria for immunotoxicity defined by Luster. For the developmental toxicity database, substances were selected from the Munro ct nl. database that contained the lowest NOELs retrieved from the literature for more than 600 compounds. After screening these, substances shelving any effect which could point to developmental toxicity as broadly defined 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 neurotoxicity 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 immune NOELs (or LOELs-lowest-observed-effect levels-when NOELs were not available),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 toxicity endpoint since data currently available do not permit the establishment of a clear causal link between endocrine active chemicals and adverse effects in humans. Therefore, this endpoint was analysed by estimating the human exposure to oestrogenic environmental chemicals and evaluating their potential 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 population but rather to subsets of susceptible individuals, and allergic risks are usually controlled by other means (i.e, labelling) than the Threshold of Toxicological Concern approach. However, as several researchers are currently examining the existence of a threshold in allergy, the possibility of determining threshold doses for food allergens was put into perspective, and the likelihood for chemical substances to induce allergy at dietary relevant doses was discussed. The analysis indicated that, within the limitation of the databases, developmental neurotoxicity and developmental toxicity were not more sensitive than other non-specific endpoints. Although the cumulative distribution of NOELs for neurotoxic compounds was significantly loner than those for other non-cancer endpoints, these substances were accommodated within the TTC of 1.5 mu g/person/day. Furthermore, the analysis demonstrated that none of the specific non-cancer endpoints evaluated 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 margin of safety. Analysis of the immunotoxicity database should that for the group of immunotoxicants examined here, the specific immunotoxic endpoint was not more sensitive than other endpoints. In other words, the distribution of immunotoxic 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 and their oestrogenic potencies were compared with that of endogenous hormones, in order to assess their impact on human health. The results are in line with scientific data obtained so far, suggesting that estrogenic compounds of anthropogenic origin, in comparison with endogenous hormones, possess only little hormonal activity lilts phytoestrogens. Results of animal studies 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. However, provided that numerous criteria need to be satisfied before sensitization 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 conservative assumptions at each step of the procedure (i.e. in data compilation and data analysis), and continually adopting a "worst case" perspective, it can be concluded that a Threshold of Toxicological Concern of 1.5 mu g/person/day provides adequate safety assurance. Chemical substances present in the diet that are consumed at levels below this threshold pose no appreciable risk. Moreover, for compounds which do not possess structural alerts for genotoxicity and carcinogenicity, further analysis mag indicate that a higher Threshold of Toxicological Concern mag he appropriate.
threshold; toxicological endpoints; structural alerts; NOEL
Settore BIO/14 - Farmacologia
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/187209
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