Alberto Mantovani from Istituto Superiore di Sanità, Roma, Italy, looks at an aspect of food safety that concerns assessing mixtures of endocrine disruptors
Endocrine disruptors (ED) may be present individually at low levels in our diet and living environment, but what about the concurrent presence of multiple EDs? And through a common route of exposure? And with common modes of action or targets? If these conditions occur, the combined exposure may raise serious concerns. The example of dioxins and dioxin-like compounds shows that cumulative risk assessment is part of the real-life of regulators and risk managers.
Assessing mixtures of endocrine disruptors
Two recent opinions of the European Food Safety Authority tackle topical issues in the assessment of ED mixtures; the combined intake of several phthalates through food contact materials as well as other sources; the presence of multiple and chemically diverse pesticide residues in food with the potential to affect the thyroid.
As of September 2019, EFSA has assessed five phthalates used in food contact materials, namely di-butylphthalate (DBP), butyl-benzyl-phthalate (BBP), bis (2-ethylhexyl)phthalate (DEHP), di-isononylphthalate (DINP) and di-isodecylphthalate (DIDP) (click here for more details). DBP, BBP and DEHP were clearly identified as EDs, because they all induce adverse effects on reproduction in laboratory rodents through a common endocrine-related mode of action, the reduction of the foetal testosterone production; moreover, the reproductive effects are the basis for calculating the health-based guidance values (HBGVs) for these chemicals. DIDP induced liver, but not reproductive, toxicity and was not considered in the cumulative assessment. DINP, while being mainly a liver toxicant, also induced a transient decrease of fetal testosterone production. Therefore, considering the concern elicited by cumulative exposure to ED, a group Tolerable Daily Intake (TDI) was established for DBP, BBP, DEHP and DINP based on similar and endocrine-related reproductive effects. DEHP was identiﬁed as an index compound since it has the most robust toxicological dataset. The group-TDI was 0.05 mg/kg bw per day, expressed as DEHP equivalents; the relative potency factors (RPFs) for the other phthalates, calculated by comparing the respective HBGVs based on reproductive effects, were 1 for DEHP, 5 for DBP, 0.1 for BBP and 0.3 for DINP.
Phthalates including Total Diet Studies
Then, is there a risk due to cumulative exposure to these phthalates? Exposure assessment using data from European institutions suffered from high analytical limits of quantiﬁcation, most likely because the analytical methods were to enforce legislative limits rather than to achieve high sensitivity. Luckily, the scientific literature provided a wealth of information on the occurrence of phthalates in food, including some Total Diet Studies (TDS). Thus, a fit-for-purpose exposure assessment could be finalised. Based on the available data, the cumulative dietary exposure to ED phthalates (expressed as DEHP equivalents) is of no concern in Europe, as the most conservative estimate reaches 23% of the group-TDI: the lowest range of estimates point to a mere 2-3% of TDI. The estimates reflect the overall dietary exposure from all sources, food contact materials as well as the environment.
However, diet is one component of aggregate exposure: phthalates are present in indoor air and dust and in a number of articles (e.g. sandals, erasers and sex toys). According to the assessment performed by the European Chemical Agency in 2017 on DEHP, DBP and BBP separately, the contribution of food to aggregate exposure in women (since pregnancy is the susceptible window to ED phthalate toxicity) was in the range 5%-25%, higher for DEHP and lower for DBP; DEHP was also the most prevalent phthalate (in terms of mg/kg body weight per day of estimated aggregate exposure), followed by DBP and then BBP.
The EFSA opinion also notes that at least another phthalate, DIBP, may have ED-related reproductive effects. While DIBP is not authorised in food contact materials, available data indicates that it might substantially add to the overall aggregate exposure, to an extent comparable to DBP; thus, DIBP deserves further attention. The available data cannot rule out that the aggregate exposure to ED phthalates would exceed the group-TDI in a fraction of highly exposed women of fertile age.
Pesticides and the thyroid
In March 2020, EFSA has published its “Cumulative dietary risk characterisation of pesticides that have chronic effects on the thyroid”. The pesticides to be considered have been previously identified when establishing cumulative assessment groups (CAGs) of pesticides for their effects on the thyroid; CAGs are based on downstream phenotypic outcomes rather than mechanisms, for both practical and scientific reasons. For many pesticides, toxicity mechanisms (different from pesticidal action) are poorly defined; meanwhile, a substance may interfere with iodine transport and/or with synthesis and/or transport and/or metabolism of thyroid hormones, all these pathways eventually leading to hypothyroidism. Two CAGs were identified, namely, for hypothyroidism (128 substances) and C-cell hypertrophy, hyperplasia and neoplasia (17 substances).
All substances were characterised by no observed adverse effect levels (NOAELs) for long-term cumulative exposure/risk assessment, derived from the most sensitive indicator, using all available information across studies, species and sexes. This brought several uncertainties, from the composition of CAGs to the role of metabolites and the inter-species extrapolation. Concerning CAG composition, weight of evidence and expert knowledge elicitation techniques were used to address the uncertainty about the total number of substances in the large CAG for hypothyroidism: active substances were allocated in subgroups of varying levels of evidence, and a median estimate of 71 was derived for the number of active substances causing hypothyroidism.
Cumulative exposure assessments were conducted of all pesticides included in the two CAGs, both by EFSA and the Dutch National Institute for Public Health and Environment (RIVM) using probabilistic modelling with different software tools: noticeably, the two assessments produced nearly identical results. The exposure calculations used monitoring data collected by the EU Member States in 2014-2016 and individual food consumption data from 10 populations of consumers from different countries, including adults, children (up to 9 years) and toddlers (up to 3 years). Exposure estimates relied on the principle of dose addition and were obtained for different percentiles of the exposure distribution, expressed as “total margin of exposure”. The alert for regulatory consideration was considered when the total margin of exposure calculated at the 99.9th percentile of the exposure distribution is below 100. For C-cell effects risk characterisation, even using the most conservative assumptions, did not raise any alert. As for hypothyroidism, the absence of alert for regulatory consideration was estimated with very high certainty (over 99%) for adults and, to a slightly lower extent, for children (95-90%) and toddlers (90-85%).
Interestingly, the exposure to the hypothyroidism CAG was predominantly driven by the occurrence of bromide ion; other important drivers were the fungicides propineb, mancozeb, ziram (all dithiocarbamates), thiabendazole, pyrimethanil and cyprodinil, and the herbicide chlorpropham. Due to the high conservativeness of the alert threshold, health concerns from chronic effects on the thyroid are very unlikely. Nevertheless, there are a few important caveats: some major pesticide metabolites, including the potent thyrostatic ED ethylene thiourea, were not included in the assessment because they were not routinely monitored; most relevant, no CAG for developmental effects mediated by thyroid disruption could be set, because of insufficient data. Thus, the assessment done till now is a major step forward within a work that is still in progress.
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