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The Impact of Plasticisers on Human Health

The bisphenol family of chemicals in plastics are common in our food and beverage supply (and in many other products) and have been implicated in many health conditions. In this article, Cliff Harvey PhD reviews the research on the implications of BPA and related chemicals on health.

Key points

  • The impact of bisphenols on health is becoming more widely studied and understood
  • There is now sufficient evidence to consider BPA a significant risk factor for health
  • Alternative bisphenols (BPAF, BPF, BPs) are likely to be as toxic as BPA
  • Bisphenols are known to be toxic to the kidneys and neurons
  • Bisphenols are known endocrine disruptors
  • They may increase DNA damage and cancer formation
  • Bisphenols may also precipitate weight and fat gain (in children and adults) and increase the risk of diabetes
  • Bisphenols might also predispose children to allergy and asthma
  • It is unclear whether current intake levels offer an appreciable risk to health, but emerging evidence suggests that previous recommended ‘safe’ intake levels could still be harmful

Bisphenols such as bisphenol A (BPA) and bisphenol S (BPS) are chemical ‘plasticisers’ that function as raw materials for the production of many plastics including storage containers, food and beverage packaging, and lacquers and sealants for a range of other products (such as the BPA or BPS containing treatments on thermal cash register receipts).1 They are one of the most common industrial chemicals that we come in contact with due to our extraordinary use of products made from plastic. These plasticisers have been found in food, house dust, rivers and lakes, and personal care products,2, 3 and in a review of 500 studies, BPA was found in greater than recommended levels in effluent, surface water, sewage, sediment, soil, air and other environments in more than 50% of samples from Europe, Asia, and North America.4 They have also been identified in human blood, saliva, and urine samples.5 While some exposure items like thermal paper, may not appreciably increase internal exposure (i.e. we don’t know exactly how well it is absorbed through the skin), it is known that BPA is transferred from thermal paper to the skin and can be absorbed,6 and we ingest the bisphenols as a result of food and beverages stored in plastic or exposed to it during processing.

There were, up until relatively recently, relatively few studies on the toxicity and effects of bisphenols but in recent years, much larger amounts of data are emerging. (See figures below)

From https://www.sciencedirect.com/science/article/pii/S0300483X18306668

BPA had typically been considered a low-risk substance with little potential for harm. However, it is now known that it can cause appreciable health harms, even at low doses,7 and is toxic to a range of animals and organisms including humans.8-10 In a study which evaluated BPA from milk alone, exposure levels were considered to be a concern to human health.11

As knowledge of the health effects of BPA have become more well known, there has been a movement towards using alternative bisphenols in its place. This has led to an increase in exposure to other bisphenol chemicals, in particular, BPAF, BPF, and BPS, and this has resulted in similar or even greater levels of exposure and accumulation of these chemicals in humans.12 The various bisphenols; BPAF, BPB, BPF, and BPS (and not just BPA),  have been shown to exhibit anti-thyroid, oestrogenic, and antiandrogenic properties. These analogues also exhibit hormone-disrupting effects, toxicity and damage to both cells and genes, reproductive toxicity, immune dysfunction, dioxin-like effects, nephrotoxicity (damage to the kidneys), and neurotoxicity (toxicity to the brain and central nervous system) and are carcinogens (cancer-causing chemicals).9, 12-14 BPA analogues are, in many cases, even more toxic than the BPA they replace. For example, BPB is more acutely toxic and cytotoxic (toxic to cells) and more oestrogenic than BPA,5 while the evidence for the toxicity of BPS is somewhere between less toxic, but most likely to be at least as toxic as BPA.3, 15

BPA analogues are, in many cases, even more toxic than the BPA they replace

From: https://www.sciencedirect.com/science/article/pii/S0300483X18306668
From: https://www.sciencedirect.com/science/article/pii/S2468227619306969

Summary of major effects of bisphenols

Overall

While there is a suggestion that in utero exposure to bisphenols leads to fat-gain in children, reviews of the evidence show conflicting results for the effects of prenatal bisphenol exposure on children’s weight and body fat levels.16 The other bisphenols used to replace BPA are also likely to increase childhood obesity.17 Chemical breakdown products from the environmental degradation of bisphenols could also be hormone disruptors.18 It is only recently (in a 2018 review of 15 studies on metabolomics of BPA) that some of the implications for metabolism in humans have been recognised, with glycolysis, Krebs cycle intermediates, oxidation of long-chain fatty acids, pentose phosphate pathway, nucleoside metabolism, branched-chain amino acid metabolism, aromatic amino acid metabolism, and sulphur-containing amino acid metabolism significantly changed after BPA exposure.19 These findings suggest that bisphenols have a complex range of toxic effects in humans.

Bisphenols have a complex range of toxic effects in humans

BPA

The majority of the research on the health effects of bisphenols has come from the study of BPA. Overall, BPA is suspected to be associated with many chronic metabolic diseases. In a major review of observational studies measuring urinary BPA and including at least 100 participants, there was found to be a significant association between BPA levels (highest vs. the lowest urinary BPA) and:

  • Diabetes (OR 1.47, 95 % CI: 1.21–1.80)
  • Overweight (1.21, 95 % CI: 0.98–1.50), obesity (1.67 , 95 % CI: 1.41–1.98)  and waist circumference (1.48, 95 % CI: 1.25–1.76)
  • Hypertension (1.41 (95 % CI: 1.12–1.79)

In prospective studies, there also appears to be a link between BPA exposure and incidence of diabetes, coronary heart disease, and weight gain.20 And while the link between BPA and type 2 diabetes is controversial, is suggested that this association is not due to chance as the studies typically show either a significant association or a trend towards a likely association.21

There appears to be a link between BPA and diabetes, coronary heart disease, and weight gain

In reviews of observational studies, there is a consistent finding of reproductive effects, however, the effects on specific hormones and reproductive outcomes are inconsistent.22 However, there are plausible and proven mechanisms by which BPA acts as a hormone disruptor and the evidence indicates that BPA is likely to increase the risk of infertility in women.23

It has also been commonly discussed in the mainstream that hormone disruptors, especially ‘xeno-oestrogens’ from plastics hasten puberty. In a review of 19 available studies, only seven showed an association between BPA and puberty.24

Other outcomes:

Kidney damage

  • BPA acts as a biomarker for renal disease and is toxic to the kidneys.9

Hormone disruption and sex-effects

  • BPA disrupts hormones by increasing oestrogen metabolism in the kidney and upregulating cytochrome p-450 aromatase activity by means of steroidogenesis.9
  • BPA is an ovarian, uterine and prostate toxicant at a level below the lowest observed adverse effect level (50 mg kg−1 body weight) as well as below the proposed safe level (4 μg kg−1 body weight).25
  • Reliable evidence shows a negative effect of BPA on sperm quality and motility.25

Cancer formation and DNA damage

  • BPA can affect cell signalling processes of growth, division, migration, and autophagy and apoptosis, increasing the risk of cancer formation and growth.26
  • Low-dose exposure could provide a significant risk for oncogenesis (cancer formation), especially breast cancer risk.10
  • The epigenetic risks from BPA exposure are typically seen at nM blood ranges (see later in this article for an explanation of how this relates to intakes) and increases in a linear fashion with higher doses.27
  • A recent (2016) review suggested that “there is substantial evidence from rodent studies indicating that early-life BPA exposures below the oral reference dose lead to increased susceptibility to mammary and prostate cancer. Based on the definitions of “carcinogen” put forth by the International Agency for Research on Cancer and the National Toxicology Program, we propose that BPA may be reasonably anticipated to be a human carcinogen in the breast and prostate due to its tumour promoting properties.”28

Pregnancy and birth outcomes

  • Recent reviews (2017-2019) reviews have demonstrated an association between BPA exposure and birth weight,29, 30 and developmental defects and miscarriage.30

Weight and fat gain

  • Higher BPA exposure is likely to increase the risk of obesity in children.17, 31
  • In adults, reviews of 18 studies (to 2015) were split between no association between BPA exposure and BMI (10 studies) but with a significant association seen in eight studies.32

Insulin resistance and metabolic disorders

  • BPA might be involved in insulin resistance and hyperandrogenism in PCOS.33

Behavioural effects

  • Early exposure to BPA is linked to increased hyperactivity.34
  • Prenatal exposure to maternal BPA is associated with higher levels of anxiety, depression, aggression, and hyperactivity in children.35

Allergy and asthma

  • There is some suggestion that BPA (and phthalates found in plastics) might also predispose children to asthma and allergies.36, 37
Locations of studies on BPA and type 2 diabetes.
From: https://link.springer.com/article/10.1007/s11356-016-7525-0

There have been fewer studies on the alternative bisphenols now being used more commonly than BPA. However, similar effects are now being demonstrated in scientific research.

BPB

  • BPB is likely to be anti-androgenic, demonstrating reduced testosterone production in human testes and reducing sperm motility, and number.5
  • It is similarly oestrogenic, and promotes developmental toxicity, oxidative stress, and reduces cortisol and cortisone.5

BPF

  • BPF is a potential carcinogen, and genotoxin (causing DNA damage).5
  • It has similar oestrogenic activity to BPA and is also anti-thyroid, and results in probable developmental toxicity, and is an oxidative toxicant.5

BPS

  • BPS has similar or lower toxicity than BPA.3
  • BPS has similar or less endocrine disruption than BPA.3
  • It also exhibits similar neurotoxicity and immunotoxicity, and lower reproductive and developmental toxicity3

What are suggested safe intakes?

A temporary tolerable daily intake of 4 μg per kilogram of body weight per day and a migration limit of 0.6 mg/kg in food from plastic materials, has been set.11 To put this in context, the recommended short-term daily tolerable intake for me (an 85 kg male) would be ~340 mcg.

The suggestion from animal and human research is that there is a likely risk from exposure levels less than recommended ‘safe’ amounts

The average daily intake in the US population is estimated to be ~25 ng per day (from BPA alone).27 This intake amount results in blood levels in the pMol range, while effects are typically seen in in vitro at nMol ranges. So, typical levels of ingestion may not result in levels sufficient to induce appreciable damage. However, when we consider the total (and rising) amounts of bisphenols, and other chemicals like phthalates that are incorporated into our food and lifestyle environment, and accumulation in the body, there might be some cause for concern. As stated earlier, the suggestion from animal and human research is that there is a likely risk from exposure levels less than these apparently ‘safe’ amounts,28 and the accumulation of both laboratory and observational evidence showing harm, further urges caution with the use of plastics.

Typical levels of ingestion may not result in levels sufficient to induce appreciable damage

Other considerations

Because of its abundance in nature, there is also concern that environmental bisphenol exposure could be damaging to plants, fungi, animals, and entire ecosystems. BPA, for example, might affect the growth and viability of many plants.38 Conversely, the use of some plants and fungi might aid bisphenol pollution control by metabolising these chemicals into non-toxic ones.38 Of particular concern is the abundant use of microplastics (pieces of plastic less than 5mm in diameter) which provide bisphenols (increasingly BPS) into the environment, and especially aquatic environments.39 Microplastics are formed through physical degradation of plastic by sun exposure, heat, and stress (such as ‘wave slap’). Bisphenols can biodegrade but this takes a long time. Interestingly, BPS increasingly used to replace BPA degrades more slowly in the environment that BPA (due to its unique bond structure).39 Breakdown products of BPA and other bisphenols that are created as plastics degrade could also exhibit endocrine activities (affecting the hormonal balance of animals) and could have other environmental and ecosystem effects as they accumulate.18

What can I do to reduce my bisphenol exposure?

Avoidance is the key to reducing your exposure to bisphenols and the best way to reduce exposure to bisphenols is to reduce the use of plastics. Some plastics are going to be unavoidable in the modern world, but we can drastically reduce our exposure to bisphenols. Remember that BPA-Free does not mean bisphenol-free.

  • Use glass storage containers wherever possible
  • Use a tempered glass or stainless-steel water container (aluminium containers contain plastic coatings)
  • NEVER microwave using plastic containers
  • Buy foods, liquids and oils in glass containers
  • If you work with thermal paper receipts, wear latex gloves

Be especially aware of heating food or beverages in plastic containers. Heat, acid, and fat all drastically increase the absorption of bisphenols by foods. So, similarly, don’t store fatty foods or beverages (like milk), or acidic foods or liquids (i.e. pickles and apple cider vinegar) in plastic bottles.

Be especially aware of heating food or beverages in plastic containers

It IS OK to store dry foods in plastic, especially bisphenol free plastics like HDTA (such as dry protein powders). However, wherever possible, it is better to store foods in glass, steel, ceramic, or wooden containers (depending on the food of course!). 

References

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2.            Pelch K, Wignall JA, Goldstone AE, Ross PK, Blain RB, Shapiro AJ, et al. A scoping review of the health and toxicological activity of bisphenol A (BPA) structural analogues and functional alternatives. Toxicology. 2019;424:152235.

3.            Qiu W, Zhan H, Hu J, Zhang T, Xu H, Wong M, et al. The occurrence, potential toxicity, and toxicity mechanism of bisphenol S, a substitute of bisphenol A: A critical review of recent progress. Ecotoxicology and Environmental Safety. 2019;173:192-202.

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16.         Gómez-Mercado CA, Mejía-Sandoval G, Segura-Cardona ÁM, Arango-Álzate CM, Hernández-González SI, Patiño-García DF, et al. Exposición a Bisfenol A (BPA) en mujeres embarazadas y su relación con la obesidad en sus hijos: Revisión Sistemática. Revista Facultad Nacional de Salud Pública. 2018;36:66-74.

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19.         Wang M, Rang O, Liu F, Xia W, Li Y, Zhang Y, et al. A systematic review of metabolomics biomarkers for Bisphenol A exposure. Metabolomics. 2018;14(4):45.

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21.         Sowlat MH, Lotfi S, Yunesian M, Ahmadkhaniha R, Rastkari N. The association between bisphenol A exposure and type-2 diabetes: a world systematic review. Environmental Science and Pollution Research. 2016;23(21):21125-40.

22.         Mínguez-Alarcón L, Hauser R, Gaskins AJ. Effects of bisphenol A on male and couple reproductive health: a review. Fertility and Sterility. 2016;106(4):864-70.

23.         Ziv-Gal A, Flaws JA. Evidence for bisphenol A-induced female infertility: a review (2007–2016). Fertility and Sterility. 2016;106(4):827-56.

24.         Leonardi A, Cofini M, Rigante D, Lucchetti L, Cipolla C, Penta L, et al. The role of bisphenol A on puberty: a critical review of the medical lierature. 2017.

25.         Tomza-Marciniak A, Stępkowska P, Kuba J, Pilarczyk B. Effect of bisphenol A on reproductive processes: A review of in vitro, in vivo and epidemiological studies. Journal of Applied Toxicology. 2018;38(1):51-80.

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28.         Seachrist DD, Bonk KW, Ho S-M, Prins GS, Soto AM, Keri RA. A review of the carcinogenic potential of bisphenol A. Reproductive Toxicology. 2016;59:167-82.

29.         Zhou Z, Lei Y, Wei W, Zhao Y, Jiang Y, Wang N, et al. Association between prenatal exposure to bisphenol a and birth outcomes: A systematic review with meta-analysis. Medicine. 2019;98(44):e17672.

30.         Pergialiotis V, Kotrogianni P, Christopoulos-Timogiannakis E, Koutaki D, Daskalakis G, Papantoniou N. Bisphenol A and adverse pregnancy outcomes: a systematic review of the literature. The Journal of Maternal-Fetal & Neonatal Medicine. 2018;31(24):3320-7.

31.         Kim KY, Lee E, Kim Y. The Association between Bisphenol A Exposure and Obesity in Children—A Systematic Review with Meta-Analysis. International Journal of Environmental Research and Public Health. 2019;16(14):2521.

32.         Oppeneer SJ, Robien K. Bisphenol A exposure and associations with obesity among adults: a critical review. Public Health Nutrition. 2015;18(10):1847-63.

33.         Hu Y, Wen S, Yuan D, Peng L, Zeng R, Yang Z, et al. The association between the environmental endocrine disruptor bisphenol A and polycystic ovary syndrome: a systematic review and meta-analysis. Gynecological Endocrinology. 2018;34(5):370-7.

34.         Rochester JR, Bolden AL, Kwiatkowski CF. Prenatal exposure to bisphenol A and hyperactivity in children: a systematic review and meta-analysis. Environment International. 2018;114:343-56.

35.         Ejaredar M, Lee Y, Roberts DJ, Sauve R, Dewey D. Bisphenol A exposure and children’s behavior: A systematic review. Journal of Exposure Science & Environmental Epidemiology. 2017;27(2):175-83.

36.         Robinson L, Miller R. The Impact of Bisphenol A and Phthalates on Allergy, Asthma, and Immune Function: a Review of Latest Findings. Current Environmental Health Reports. 2015;2(4):379-87.

37.         Xie M-Y, Ni H, Zhao D-S, Wen L-Y, Li K-S, Yang H-H, et al. Exposure to bisphenol A and the development of asthma: A systematic review of cohort studies. Reproductive Toxicology. 2016;65:224-9.

38.         Xiao C, Wang L, Zhou Q, Huang X. Hazards of bisphenol A (BPA) exposure: A systematic review of plant toxicology studies. Journal of Hazardous Materials. 2019:121488.

39.         Fang Z, Gao Y, Wu X, Xu X, Sarmah AK, Bolan N, et al. A critical review on remediation of bisphenol S (BPS) contaminated water: Efficacy and mechanisms. Critical Reviews in Environmental Science and Technology. 2019:1-47.

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