Open letter to the editor – Pediatrics – re: Food Additives and Child Health
The American Academy of Pediatrics (AAP) has put forth a set of policy recommendations based on a hypothesis that the presence of certain chemicals in the diet suggests potential adverse effects on children’s health. “Phthalates” are among the chemical names in the policy recommendations and accompanying technical report (Trasande et al. 2018). To prevent misunderstandings that could arise from these documents, we would like to point out the following:
- People typically are not exposed to phthalates through microwaveable plastics, and not all recycling code 3 vinyl contains phthalates)
Phthalates are primarily used as softening agents to make rigid vinyl flexible, and are typically not used in rigid vinyl products identified by recycling code 3. Hence, only flexible vinyl products, such as flooring, wire and cable, roofing, etc., would contain phthalates or other plasticizers. A recent US FDA evaluation of food contact packaging such as food wraps and cap gaskets of jarred food products confirmed that these products contain mostly non-phthalate plasticizers (Carlos et al, 2018). For example, the only US food-contact clearance for di-isononyl phthalate (DINP) is 21 CFR §178.3740 which permits its use in a narrow range of food-contact applications at temperatures not exceeding room temperature. Thus, this type of plasticizer is unlikely to be present in a microwaveable food contact article.
- DINP and DIDP have received multiple health and safety evaluations from global regulatory agencies, which have concluded they expect no risks via food under existing conditions of use.
Trasande et al. note that DINP and DIDP “have not been banned or restricted by regulatory agencies.” This is with good reason. DINP/DIDP are two of the most studied phthalates and have been evaluated multiple times, by multiple regulatory agencies over the past 20 years. For example, the European Commission (EC) published two rigorous risk assessment reports on DINP and DIDP in 2003 (EU RAR, 2003) and 2013 (European Chemicals Agency, 2013; European Commission, 2014). In both cases, these European Union (EU) agencies found no risk expected from dietary exposure to DINP or DIDP (or in combination) for children (as young as 0-6 months) and adults. The specific comment by European Chemical Agency (ECHA) is: “no risk is expected from combined exposure to DINP and DIDP for children exposed via food and the indoor environment” (European Chemicals Agency, 2013). More recently, ECHA’s Committee for Risk Assessment (RAC) published a final consensus opinion that no classification for adverse effects to reproduction or development was warranted for DINP under the EU’s classification, labelling and packaging (CLP) regulation (European Chemicals Agency, 2018). Similar in-depth hazard and risk evaluations on DINP or DIDP have also been conducted in Canada and Australia. Both have reached the same conclusion, that DINP and DIDP do not pose a health concern for existing consumer applications. Furthermore, in 2011, the UK Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT), an independent scientific committee that provides advice to the UK Food Standards Agency, evaluated the risk of dietary exposure to phthalates, including DINP and DIDP. The committee concluded that the estimated dietary exposures “do not indicate a concern for health of consumers.” In October 2017, the New Zealand Ministry for Primary Industries (MPI) released a report on the risk characterization of packaging chemicals (phthalates, printing inks/photoinitiators) in food. The MPI concluded that for all but one of the compounds evaluated (including DINP and DIDP), “dietary exposure estimates showed no risk to human health.” In March 2018, Food Standards Australia New Zealand (FSANZ) released a survey on the health risks of plasticizers (including DINP and DIDP) in Australian foods. Overall, FSANZ concluded that exposures to these chemicals in food packaging “are low and unlikely to pose a public health and safety concern.”
In the US, the Consumer Product Safety Commission (CPSC) recently published a final rule based on an evaluation of certain phthalates, including DINP and DIDP, that used a number of conservative assumptions. The CPSC’s rule restricts the use of DINP in toys and childcare articles. The interim restriction on DIDP was lifted, as the CPSC concluded that DIDP does not cause adverse effects on male reproductive development and other risks attendant to its use are low.
- Association is not causation
Trasande et al note associations in cross-sectional studies between DINP and DIDP exposure and insulin resistance and systolic blood pressure in children and adolescents. They cite two articles (also by Trasande et al), but do not carry over the caveat from one of them that “causation cannot be inferred from a cross-sectional study” (Attina & Trasande, 2015). That article, regarding insulin resistance, also points to several potential confounders that were unmeasured and thus could not be controlled for in their study. Furthermore, Attina & Trasande provide a more plausible alternative explanation to their findings: that insulin-resistant children have unhealthy eating habits that include consumption of packaged food that happens to contain higher phthalate levels than the unpackaged foods consumed by healthier children. This alternative explanation would then suggest that the association of DINP/DIDP with insulin resistance is merely a non-causal association that simply occurs by default (Sharpe & Drake, 2013).
Trasande et al. also cite Trasande & Attina (2015) that concluded that there was an association between DINP and DIDP and increased blood pressure in children and adolescents. However, the evidence provided in that paper was poor, inconsistent and likely of little to no clinical relevance. First, this article identified a significant association with systolic blood pressure, but not diastolic blood pressure, increased risk of pre-hypertension, triglycerides and high-density lipoprotein (HDL) with DINP and DIDP. Secondly, as the authors note, the association with systolic blood pressure appeared to be small and of limited clinical relevance. The same article also raised some significant limitations associated with cross-sectional studies, including the problem of unmeasured confounders, reverse causation (i.e. that children and adolescents with increased systolic blood pressure have increased urinary excretion of phthalates simply because they consume higher levels of packaged foods, which foods simultaneously raise their blood pressure and their phthalate exposure), and the use of spot samples (which the authors considered “weak indices of exposure,” since half-lives of phthalate metabolites are typically <48 hours) that are not indicative of the temporal variability of DINP/DIDP exposure over time. In addition, Trasande & Attina (2015) erroneously claimed that DINP and DIDP “have not been substantially studied for toxicity in laboratory studies.” In fact, the 2018 ECHA RAC assessment of DINP included at least five (5) 90-day toxicity studies and four (4) lifetime studies in rodents, none of which identified any cardiovascular effects of DINP, even at high doses. As we have also noted above, these substances have been the subject of multiple risk evaluations by several regulatory agencies, especially with respect to dietary exposure. In citing only ‘supporting’ references, Trasande et al failed to cite other independent review articles that conclude that the available evidence is not sufficient to establish a relationship between phthalates and obesity, diabetes or cardiovascular effects in humans (Beydoun et al, 2013; Buckley et al, 2016; Goodman et al, 2014; Kuo et al, 2013; Sharpe & Drake, 2013).
- Studies of DINP and DIDP show no evidence of hypospadias and cryptorchidism, changes in men’s hormone concentrations or morphological changes in sperm
The 2018 ECHA RAC opinion on DINP clearly stated that DINP does not induce gross-structural malformations such as hypospadias and cryptorchidism (European Chemicals Agency, 2018). The same report also reviewed several epidemiological studies to evaluate a potential association between DINP exposure and adverse reproductive effects (Joensen et al, 2012; Mieritz et al, 2012; Specht et al, 2015; Specht et al, 2014). These studies examined more than 1,500 boys and young men across Europe and found no evidence that DINP caused adverse changes to fertility measures such as sperm parameters and hormone levels.
High molecular weight phthalates have been used safely in consumer and commercial applications for more than 50 years, ranging from use in building and construction, automotive and many other applications. Aside from their history of safe use, these phthalates offer significant benefits for which similarly effective and safe alternatives (subjected to the same level of scientific and regulatory scrutiny) are not readily available. High molecular weight phthalates are among of the most studied chemicals in commerce today and rigorous evaluations of these phthalates by regulatory agencies around the world continue to confirm that these chemicals are safe in their current applications. More importantly, several regulatory agencies have re-affirmed the safety of dietary exposure to low levels of phthalates as used in food packaging.
Attina TM, Trasande L (2015) Association of Exposure to Di-2-Ethylhexylphthalate Replacements With Increased Insulin Resistance in Adolescents From NHANES 2009–2012. The Journal of Clinical Endocrinology and Metabolism 100: 2640-2650.
Beydoun H, Khanal S, Zonderman AB, Beydoun M (2013) Is Exposure to Bisphenol-A and Phthalates Associated with Obesity, Metabolic Disturbances and Insulin Resistance among U.S. adults? The FASEB Journal 27: 630.624-630.624.
Buckley JP, Engel SM, Mendez MA, Richardson DB, Daniels JL, Calafat AM, Wolff MS, Herring AH (2016) Prenatal Phthalate Exposures and Childhood Fat Mass in a New York City Cohort. Environ Health Perspect 124: 507-513.
Carlos KS, de Jager LS, Begley TH (2018) Investigation of the primary plasticisers present in polyvinyl chloride (PVC) products currently authorised as food contact materials. Food additives & contaminants Part A, Chemistry, analysis, control, exposure & risk assessment 35: 1214-1222.
EU RAR (2003) 1,2-BENZENEDICARBOXYLIC ACID, DI-C8-10-BRANCHED ALKYL ESTERS, C9-RICH AND DI-“ISONONYL” PHTHALATE (DINP); CAS Nos: 68515-48-0 and 28553-12-0 EINECS Nos: 271-090-9 and 249-079-5 – RISK ASSESSMENT https://echa.europa.eu/documents/10162/83a55967-64a9-43cd-a0fa-d3f2d3c4938d.
European Chemicals Agency (2013) Evaluation of new scientific evidence concerning DINP and DIDP in relation to entry 52 of Annex XVII to REACH Regulation (EC) No 1907/2006. https://echa.europa.eu/documents/10162/31b4067e-de40-4044-93e8-9c9ff1960715.
European Chemicals Agency (2018) Opinion proposing harmonised classification and labelling at EU level of 1,2-Benzenedicarboxylic acid, di-C8-10-branched alkylesters, C9- rich;  di-“isononyl” phthalate;  [DINP]. https://echa.europa.eu/documents/10162/56980740-fcb6-6755-d7bb-bfe797c36ee7.
European Commission (2014) Phthalates entry 52 Commission conclusions on the review clause and next steps.
Goodman M, LaKind JS, Mattison DR (2014) Do phthalates act as obesogens in humans? A systematic review of the epidemiological literature. Critical Reviews in Toxicology 44: 151-175.
Joensen UN, Frederiksen H, Blomberg Jensen M, Lauritsen MP, Olesen IA, Lassen TH, Andersson AM, Jorgensen N (2012) Phthalate excretion pattern and testicular function: a study of 881 healthy Danish men. Environ Health Perspect 120: 1397-1403.
Kuo C-C, Moon K, Thayer KA, Navas-Acien A (2013) Environmental Chemicals and Type 2 Diabetes: An Updated Systematic Review of the Epidemiologic Evidence. Current diabetes reports 13: 831-849.
McKee R, Adenuga M, Carrillo J-C, Cawley L (2015) Characterization of the Toxicological Hazards of Hydrocarbon Solvents. Critical Reviews in Toxicology 45: 273-366.
Mieritz MG, Frederiksen H, Sorensen K, Aksglaede L, Mouritsen A, Hagen CP, Skakkebaek NE, Andersson AM, Juul A (2012) Urinary phthalate excretion in 555 healthy Danish boys with and without pubertal gynaecomastia. International journal of andrology 35: 227-235.
Sharpe RM, Drake AJ (2013) Obesogens and obesity—An alternative view? Obesity 21: 1081-1083.
Specht IO, Bonde JP, Toft G, Lindh CH, Jönsson BAG, Jørgensen KT (2015) Serum Phthalate Levels and Time to Pregnancy in Couples from Greenland, Poland and Ukraine. PLOS ONE 10: e0120070.
Specht IO, Toft G, Hougaard KS, Lindh CH, Lenters V, Jonsson BA, Heederik D, Giwercman A, Bonde JP (2014) Associations between serum phthalates and biomarkers of reproductive function in 589 adult men. Environ Int 66: 146-156.
Trasande L, Attina TM (2015) Association of Exposure to Di-2-Ethylhexylphthalate (DEHP) Replacements With Increased Blood Pressure In Children and Adolescents. Hypertension 66: 301-308.
Trasande L, Shaffer RM, Sathyanarayana S (2018) Food Additives and Child Health. Pediatrics 142: e20181410.
Zota AR, Calafat AM, Woodruff TJ (2014) Temporal trends in phthalate exposures: findings from the National Health and Nutrition Examination Survey, 2001-2010. Environ Health Perspect 122: 235-241.
 The US and EU have conservatively placed restrictions on DINP and, in the EU, DIDP, specifically for certain toys and childcare articles.
 We note that the CPSC’s conclusions on DINP are at odds with the conclusions from Health Canada, ECHA RAC and Australia NICNAS, which found no concern for reproductive effects from DINP. On the other hand, these agencies are unanimous in finding no concern for reproductive effects from DIDP.
 It is interesting that for every endpoint where a significant association was not found (HDL, triglycerides and pre-hypertension), the authors claim that this was as a result of a lack of sufficient power in a study population of 1,329.