ENDOCRINE DISRUPTION-An Inevitable Risk

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Endocrine disruptor (ED) is defined as “an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations” (1). ED can cause several adverse effects on exposed individuals and/or their offspring. Adverse effects include cancer, behavior alterations, neurodevelopmental delays or reproductive disorders, immune disorders, and many others. The effects depend on the affected hormonal system (estrogenic, thyroidal, etc.) and the moment of exposure (fetal development, childhood, puberty, etc.). Effects can vary based on gender too. ED effects can be inheritable to offspring from their exposed parents.  A large number of natural and synthetic substances, such as pharmaceuticals, dioxin, and dioxin-like compounds, polychlorinated biphenyls, DDT and other pesticides, and bisphenol A (BPA) can cause endocrine disruption (2). World Health Organization (WHO) attributes mostly endocrine disruptors to man-made or synthetic rather than natural.  ED evaluation has few challenges because it is difficult to obtain experimental evidence that demonstrates disruption in fetal life, during childhood and puberty. Additionally, until now there is no single validated system which could detect endocrine disruption due to the inherent complex mode of actions involved in the endocrine hormonal system.

Endocrine Disruptors in daily life

EDs, being hormonal manipulators in the human body and in other living beings of the environment, can have a serious toll on growth, developmental, and reproductive components of life. To illustrate here, we have chosen the most prominent and the widely occurring EDs in our real life: BPA. BPA is most commonly used in plastics, that can deceive the body by mimicking as sex hormone-Estrogen. BPA can cause breast cancer, reproductive problems, obesity, cardiovascular problems, and early puberty. Phthalates, abundantly available in plastic food containers and children’s toys, can cause the early death of testicular cells and result in lower sperm, low motile sperms, defects in the male reproductive system, diabetes, and thyroid irregularities. Although we lack direct evidence from clinical/epidemiological studies on humans, Diethylstilbestrol (DES) has shown adverse reproductive effects on both the sexes with convincing clinical evidence (3). In utero exposure to DES in pregnant women resulted in abnormal cervical, uterine, and oviduct anatomy with vaginal adenocarcinoma, subfertility, and infertility, and ectopic pregnancy.  The hazards triggered by EDs on human health lead to socio-economic burden range from € 46-288 billion per year in the European Union according to the report released by University of  Utrecht (4)

Case Studies

In the year 2000, the feminization of fish was detected in the Llobregat River basin of Spain. The levels of alkyl phenols (nonyl phenol ethoxylate and octyl phenol ethoxylate) measured in the water and sediments were in correlation with estrogenic effects in fish species, such as abnormally high concentrations of plasma vitellogenin in carps (vitellogenin is an egg yolk precursor protein which is used as an indicator of exposure to estrogenic compounds), and the presence of intersex fish (fishes having both male and female reproductive organs) (5). In Baltic sea, the population of seals were reduced substantially due to impaired fertility in female seals that included, abortions, occlusions of the uterus and partial or complete sterility. In addition, adrenal cortex hyperplasia, skull lesions, and malformed claws were noticed in the seals. The manifestation of adrenal hyperplasia in the seals is an apparent effect of endocrine disruption. The seals were detected with high concentrations of dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCB) concentrations. Furthermore, methyl sulfone-DDE (MeSO2-DDE), a DDT metabolite, was also evidenced in high concentrations (6). In a nested case-control study in France; of 1442 newborn males, there were 39 cases of genital malformation (2.70%), with 18 cases of cryptorchidism (1.25%), 14 of hypospadias (0.97%), 5 of micropenis (0.35%) and 2 of 46, XY disorders of sexual differentiation (DSD; 0.14%). A significant correlation was reported between newborn cryptorchidism, hypospadias or micropenis and parental occupational exposure to pesticides [odds ratio (OR) = 4.41; 95% confidence interval (95% CI), 1.21-16.00] (7). High levels of phthalates were reported in serum samples of 28 of 41 thelarche patients (premature breast development without other signs of puberty) in Puerto Rico. The phthalates identified are dimethyl, diethyl, dibutyl, and di-(2-ethylhexyl) phthalates and its major metabolite mono-(2-ethylhexyl) phthalate, were classified as EDs. These results demonstrated a plausible relationship between plasticizers having estrogenic and antiandrogenic activity and premature breast development (8).

Risk Assessment

Risk assessment is the process of evaluation of scientific data to take a scientific basis for the decision to mitigate the chemical risk to both human and environment. It is always recommended to have the data from standardized and validated assays by the Organization for Economic Co-operation and Development (OECD). However, the traditional approach of risk assessment has proven inadequate for the following facts:

  1. Due to the inherent nature of endocrine circulation hormones with low levels in the body, a small change can trigger wide biological responses. Therefore, low dose effect might differ from the effects observed at a high dose. Hence, the standard toxicity tests do not detect the effect caused by these EDs at low concentrations. Moreover, the concept of the threshold could not be assumed, and endocrine disrupting chemical follows non-monotonic dose-response relationship.
  2. EDs would have long latency and most likely the effect would be witnessed in the next/future generations.
  3. The ubiquity of exposure.
  4. Vulnerability to an ED mostly depends on exposure at certain developmental periods.
  5. The combined effect of EDs. Currently, the policy primarily entrusts largely on the data produced from well-conducted guideline studies evaluating the effects of high doses of chemicals in relation to human exposure.

Risk assessment as per OECD

OECD formulated a conceptual framework to assess EDs by measuring at different biologicals levels (ranging from biochemical to organism and population) and establish a relationship between a physiological response mediated via a hormone system and adverse effects manifested at the organism or sub-population level (9).

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Figure 1: Adopted from OECD Conceptual Framework

Recommendations

As there is no standard risk assessment methodology available for EDs, the following recommendations are worthy to consider (10)

  • Must include a study with low doses possibly no threshold and no absolute potency caused by disparities depending on the hormonal systems and many other factors.
  • Maintain a balance between the examination of basic mechanisms and integrated biological outcomes at different phases of life, thereby revealing both known and unknown effects.
  • Include the most sensitive endpoints, relevant to human and ecological health.
  • Include hormonal systems in addition to estrogen, androgen, and steroidogenesis; and thyroid hormone pathways.
  • The results of all these ED chemical identification tests should be transparent and available to the public.
  • It should be ensuring that regulatory authorities can identify chemicals that intervene with hormone function and classify them as EDs based on a realistic standard of scientific evidence, to minimize the possibility of mischaracterization of harmful chemicals. Regulatory authorities should also have transparent processes in such cases where sufficient evidence is not available to evaluate a chemical for ED effects.

Did you know? The thermal-paper receipts you get while shopping has BPA!

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References

  1. Endocrine Disruptors, European commission, 2016, available at: http://ec.europa.eu/environment/chemicals/endocrine/definitions/endodis_en.htm.
  2. Endocrine Disruptors, National institute of Environmental Health Sciences, 2019, available at:
  3. https://www.niehs.nih.gov/health/topics/agents/endocrine/index.cfm.
  4. Diamanti-Kandarakis, Evanthia et al. “Endocrine-disrupting chemicals: An Endocrine Society scientific statement” Endocrine reviews vol. 30,4 (2009): 293-342.
  5. Ingrid Rijk, Majorie van Duursen, Martin van den Berg “Health cost that may be associated with Endocrine Disrupting Chemicals” Institute for Risk Assessment Sciences, 2016.
  6. Dolores Romano Mozo “Endocrine Disruptors: solutions to new challenges” Instituto Sindical de Trabajo, Ambiente y Salud (ISTAS), 2002.
  7. Cynthia A. de Wit “Effects of endocrine disruptors in wild birds and mammals” The Norwegian Academy of Science and Letters, 2006.
  8. Gaspari L, Paris F, Jandel C, Kalfa N, Orsini M, Daurès JP, Sultan C “Prenatal environmental risk factors for genital malformations in a population of 1442 French male newborns: a nested case-control study” Hum Reprod. 2011 Nov;26(11):3155-62.
  9. Colón I1, Caro D, Bourdony CJ, Rosario O “Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development” Environ Health Perspect. 2000 Sep;108(9):895-900.
  10. “Endocrine Disrupting chemicals-OECD” available at: http://www.oecd.org/chemicalsafety/testing/OECD%20Work%20on%20Endocrine%20Disrupting%20Chemicals.pdf.
  11. “Endocrine-Disrupting chemicals in the European Union” Endocrine Society, 2018.

Authors’ Profile

Prasanna Krishna

Prasanna Krishna, Executive – Toxicology at FMD K&L

Prasanna is a Toxicologist with 3 years of experience in designing and conducting toxicity studies for pesticides, pharmaceutical, and nutraceutical products. He has expertise in assessing the safety of chemicals used in cosmetic and OTC products.

Priyanka Pandey

Priyanka Pandey, Executive – Toxicology at FMD K&L 

Priyanka is a trained toxicologist with a master’s degree in Toxicology from Jamia Hamdard, New Delhi. She has more than 3 years of work experience in toxicology, cosmetic product safety assessment, and product data management. Her expertise includes toxicology, risk assessment, and regulatory affairs, etc.