Toxic cocktails? Risk assessment of multiple exposures to endocrine disruptors


Endocrine disruptors (EDs), see thededicated area of the Istituto Superiore di Sanità website, are often present individually at low levels in our diet and environment. However, the risk of multiple exposures must be assessed: when exposure occurs through a single modality (e.g., in the diet) and/or EDs have common action or target, the situation may become worrisome.

Phthalates in MOCAs, EFSA Assessment (2019)

In September 2019, the European Food Safety Authority (EFSA) assessed the risks associated with five phthalates used in MOCAs (Food Contact Materials and Objects) (1,2). DBP, BBP and DEHP are EDs with adverse effects on reproduction in laboratory rodents. Their action on the endocrine system follows an identical pathway, the reduction of fetal testosterone, with clear harm to male reproductive development (increased congenital abnormalities at birth and infertility in adults). DINP in turn also induces a transient drop in testosterone in the fetus.

EFSA has established aTolerable Daily Intake (TDI) for the group of the first four phthalates-DBP, BBP, DEHP, and DINP-on the basis of common endocrine disrupting effects. Based on available data, cumulative dietary exposure to ED phthalates from all sources (MOCAs and the environment) poses no risk in Europe. (3) In fact, the most conservative estimates indicated an exposure level of 23 percent of the TDI defined for the group of substances under consideration.

Phthalates, aggregate exposure

Diet, nonetheless, is only one component of aggregate exposure to phthalates, which are also present in indoor air, dust and numerous everyday objects. (4)

The European Chemical Agency (ECHA), in 2017, had estimated the contribution of diet to aggregate (i.e., from all sources) phthalate exposure in women (since pregnancy is the condition most vulnerable to endocrine effects) in the range of 5%-25%. (5)

Available data (on exposure through MOCAs alone) therefore do not allow us to rule out the possibility that aggregate exposure to ED phthalates may actually exceed the safe thresholds in the groups with higher exposure (e.g., due to dietary and/or lifestyle) in the most vulnerable consumer category, women of childbearing age.

Cumulative exposure to pesticides with chronic effects on the thyroid gland. EFSA Opinion (2020)

In March 2020 EFSA published the opinion ‘Cumulative dietary risk characterization of pesticides that have chronic effects on the thyroid‘ (6,7). The assessment begins a long journey initiated by EFSA to arrive at a scientific approach to the problem of multi residues, i.e., the presence of multiple pesticide residues (each residue the maximum legal limit) in a major fraction of plant foods (more than 20 percent). The opinion reports on the possible cumulative risk assessment of a number of pesticides with effects on the thyroid gland(Cumulative assessment grouping, CAG). According to the approach developed by EFSA, it was based on the ‘phenotypic’ effects (i.e., the changes found on the thyroid gland in tests with laboratory rodents), rather than the mechanisms that cause them. In fact, the mechanisms may be disparate, as a substance may interfere with iodine transport and/or synthesis and/or transport and/or metabolism of thyroid hormones: however, all these pathways eventually lead to hypothyroidism. The CAG included more than 70 active ingredients, mainly fungicides.

All substances examined have been characterized on the basis of respective dose levels that do not cause harmful effects on the thyroid gland (No Observed Adverse Effect Levels, NOAELs) in long-term laboratory animal tests, considering data collected across all studies, in different species and in both sexes. This led to having to consider the inevitable scientific uncertainties in the composition of CAGs, particularly regarding the role of metabolites and the extrapolation of data across multiple species. (8)

Exposure levels

Exposure levels were calculated using monitoring data collected by member states from 2014-2016 and individual food consumption data from 10 populations in different European countries (adults, children and infants aged 1-3 years). Estimates were obtained from different percentiles on the distribution of exposure levels, expressed in ‘total marginofexposure’ (‘total margin of exposure‘).

The alert level-for the purpose of considering possible recommendations to the European legislature-was agreed upon in the total margin of exposure below 100 referring to the 99.9 percentile of the exposure distribution (in practice, to the most exposed consumer out of 1000 subjects. Based on the available data, it was concluded that alertness is absent (with certainty >99%) for adults and, with gradually lower certainty, for children (95-90%) and infants (90-85%). Because the approach was very conservative, concerns about chronic effects on the thyroid were thus considered to be very unlikely.

Interim conclusions

The conclusions of the aforementioned opinion contain two important reservations, which also emerged from the public consultation that preceded the publication of the final opinion. Insufficient data did not allow:

– include in the evaluation some important metabolites with effects on thyroid of currently used pesticides, as these metabolites are not included in the monitoring data, (9)

– define a CAG to analyze developmental effects mediated by thyroid dysfunction: while we know that the thyroid is particularly important for prenatal and child development, the NOAEL definition for such effects is still in flux.

Thus, the analyses conducted so far are an important step forward in scientific risk assessment, which is still ongoing in its considerable complexity. (10)

Alberto Mantovani

(translation from English and notes edited by Dario Dongo)


(1) Dario Dongo, Luca Foltran. Phthalates and BPA in the human organism. GIFT (Great Italian Food Trade). 9.11.18,

(2) EFSA (2019). Update of the risk assessment of di-butylphthalate (DBP), butyl-benzyl-phthalate (BBP), bis(2-ethylhexyl)phthalate (DEHP), di-isononylphthalate (DINP) and di-isodecylphthalate (DIDP) for use in food contact materials. EFSA Journal 2019;17(12):5838. doi: 10.2903/j.efsa.2019.5838

(3) Dario Dongo. Chemical toxicity of food contact materials, researchers appeal. GIFT(Great Italian Food Trade). 12.3.20,à-chimica-dei-materiali-a-contatto-con-gli-alimenti-appello-dei-ricercatori

(4) Dario Dongo. Toxic chemicals in everyday objects, the British report. GIFT(Great Italian Food Trade). 7/20/19,

(5) ECA (2017). Opinion on an Annex XV dossier proposing restrictions on four phthalates (DEHP, BBP, DBP, DIBP).

(6) Dario Dongo. Pesticides, we are all guinea pigs of Big 4. GIFT(Great Italian Food Trade). 8/23/19,

(7) EFSA (2020). Cumulative dietary risk characterisation of pesticides that have chronic effects on the thyroid. EFSA Journal, April 2020 18(4). doi: 10.2903/j.efsa.2020.6088

(8) Regarding the CAG composition, uncertainty was addressed by evaluation of scientific evidence and elicitation techniques. A median estimate of 71 was derived for the number of active ingredients causing hypothyroidism. The main CAG components were the bromide ion, followed by the fungicides propineb, mancozeb, ziram (all dithiocarbamates), thiabendazole, pyrimethanil, and cyprodinil, and the herbicide chlorpropham

(9) Dario Dongo. Endocrine disruptors, a new database reveals Brussels’ omissions. GIFT(Great Italian Food Trade). 12.6.20,

(10) Dario Dongo. Pesticides and the microbiome, interview with Prof. Alberto Mantovani. GIFT(Great Italian Food Trade). 5/22/19,

Alberto Mantovani

Toxicologist, research director of the Istituto Superiore di Sanità (ISS), former president of the European Society of Teratology. As well as historical member, for 15 years, of the scientific panel on feed and pesticides at EFSA (European Food Safety Authority) where he continues to work as an external expert.