In 1962, Rachel Carson described the effects of dichlorodiphenyltrichloroethane (DDT) on development and reproduction. Less than a decade later, Herbst and her colleagues documented a group of patients in Boston (USA) with vaginal adenocarcinoma as a result of prenatal use of the drug diethylstilbestrol. During this time, two assumptions were common: the Paracelsian notion that " dose sola facit venenum ", and the belief that rarely synthetic chemicals could alter hormonal and homeostatic responses and therefore contribute to disease and dysfunction. .
Over the past 50 years, both of these assumptions have proven imperfect . Many studies have identified the effects of various exogenous chemicals on endocrine processes and functions, exposing the important need for a change in scientific theory. These endocrine disrupting chemicals (EDCs) are not malicious pharmaceuticals or rare contaminants.
A review by the FDA identified more than 1,800 chemicals that disrupt at least one of three endocrine pathways (estrogens, androgens, and thyroid).
320 of 575 chemicals examined at the direction of the European Commission showed evidence or potential evidence of endocrine disruption.
Reports from various non-governmental organizations and government agencies describe the serious adverse effects of EDCs on endocrine processes during periods of development and the long latency period between exposure and disease as a result of early exposure to chemicals such as DDT. , which has been associated with the incidence of breast cancer after half a century later.
This article seeks to update the 2015 findings of an expert panel commissioned by the Endocrine Society that led to the identification of 15 exposure-outcome associations with a likelihood of causality and to identify new exposure-outcome associations of concern, especially with respect to chemicals such as perfluoroalkyl and polyfluoroalkyl substances (PFAS) and polybrominated biphenyl ethers (PBDEs) and by including various outcomes such as anogenital distance and prostate cancer.
The authors have focused on synthetic chemicals that are currently in circulation and not on remaining compounds, such as DDT, other organochlorine pesticides, polychlorinated biphenyls (PCBs), and dioxins and furans.
Wherever possible, findings related to newer chemicals that are replacing removed or banned chemicals will be emphasized. Subsequent sections describe evidence supporting previously identified or increasingly likely associations of EDC with perinatal, neurodevelopmental, metabolic, and reproductive outcomes.
Perinatal outcomes
Fetal growth, length of gestation, and especially low birth weight and preterm birth, are important predictors of health in adulthood. There is now a greater understanding that environmental exposures (especially EDCs) can induce the so-called thrifty phenotype , in which a conservatively programmed fetal metabolism adapts poorly to the ex utero environment , resulting in an early increase in adiposity. in childhood and later cardiovascular risk.
EDCs have been shown to shorten gestation, impair intrauterine growth, and disrupt metabolic programming in laboratory studies.
Additionally, anogenital distance measurements obtained at birth are known to progress into adulthood and predict infertility and reduced sperm count. The association between prenatal exposure to EDCs and perinatal outcomes has not been previously evaluated in terms of probable evidence of causality. This paper identified three notable associations: PFAS and reduced birth weight, phthalates and preterm birth, and phthalates and reduced anogenital distance in male offspring.
> Birth weight
Human studies have paid substantial attention to the associations of prenatal EDC exposure with fetal growth and birth weight. Previous research identifying decreases in birth weight in relation to maternal prenatal PFAS concentrations has been corroborated by a study published in 2017, which suggested that changes in maternal glucose concentrations act as mediators.
A meta-analysis of 24 studies reported a change in birth weight of −10.5 g per ng/ml increase in perfluorooctanoic acid (PFOA) concentration in maternal or umbilical blood, with a larger effect size in the studies who recorded exposure late in pregnancy (i.e., second or third trimester) compared with those who recorded exposure before conception or during predominantly the first trimester.
The increase in effect size is notable given the potential for confounding or reverse causality, or both, in studies that rely on exposure assessment in late pregnancy. The evidence for associations of PBDEs, phenols, and phthalates with birth weight is not as strong, including several studies that did not show significant results.
> Premature birth
Premature birth is a multifactorial condition that can sometimes have serious long-term consequences. Studying preterm birth poses many specific challenges. In particular, human studies generally do not distinguish between preterm births on the basis of different proximal causes or clinical contexts, potentially reducing the ability to discern EDC-related effects that might act along specific biological pathways.
There is strong evidence of a relationship between di-2-ethylhexyl phthalate (DEHP) and preterm birth, with associations observed in several high-quality studies, including some studies that rely on repeated samples taken during pregnancy to assess exposures. .
In the LIFECODES study , several phthalates were shown to be associated with markers of oxidative stress in pregnancy, which mediated part of the associations observed between DEHP metabolites and preterm birth observed in this population. Adverse effects of dibutyl phthalate (DBP) have been reported in at least two studies that used biomarkers of exposure.
Another study noted an increased rate of premature births in women with high exposure to DBP from taking mesalazine during pregnancy. Other phthalate compounds, such as diisobutylphthalate and diethyl phthalate, have also been associated with an increased risk of preterm birth, but in fewer high-quality studies.
Studies of associations of PFAS and phenols with preterm birth were inconsistent, and there was not enough evidence on organophosphate pesticides, pyrethroids, PBDEs, or organophosphate flame retardants (OPFRs) to draw conclusions.
> Anogenital distance
Many studies have examined the relationship between EDCs and anogenital distance, the distance between the anus and genitals (scrotum or penis in boys, clitoris in girls), which is assumed to reflect the androgenicity of the intrauterine environment. In children, most studies of high- and low-molecular-weight phthalates measured in prenatal urine or umbilical cord blood reported associations with shorter anogenital distance (a feminizing effect).
Additionally, one study showed an association between longer anogenital distance and exposure to low molecular weight phthalates. Another study observed associations between a shorter anogenital distance and exposure to mono-2-ethylhexyl phthalate (MEHP; a metabolite of DEHP) and between a longer anogenital distance and the summed metabolites of DBP (low molecular weight), and a study found no associations. In girls, anogenital distance and anogenital index were not clearly associated with in utero exposure to EDCs.
neurological development
Prenatal exposure to EDCs may affect fetal neurodevelopment through at least two distinct hormonal pathways.
- Because the fetus depends on the transplacental supply of thyroid hormone until the second trimester, maternal thyroid imbalance can have permanent and lifelong neurodevelopmental consequences for children, including attention deficit disorder, autism spectrum disorder, and cognitive and behavioral dysfunction.
- Disruption of sex hormone function can also induce dimorphic effects on brain development.
This paper identified additional evidence to support associations of prenatal exposure to PBDEs and organophosphate pesticides with decreases in intelligence quotient (IQ); PBDEs, BPA, organophosphate pesticides and pyrethroids with behavioral results; and organophosphate pesticides and pyrethroid pesticides with autism spectrum disorder.
> Prenatal and perinatal exposure and infant cognition
The evidence in humans for the cognitive effects of prenatal and perinatal exposure to EDCs is strongest for organophosphate pesticides and PBDEs. Although a longitudinal study of prenatal exposure to organophosphate pesticides did not find an association with childhood cognition, six studies showed decreases in IQ, and one of these studies also noted parietal and cortical changes consistent with the neuropsychological deficits found.
Organophosphate pesticides have increasingly been replaced by pyrethroids, for which one longitudinal study reported an adverse association between prenatal exposure and childhood cognition, while another study did not.
Regarding PBDEs, except for two small studies (n < 70), all studies showed negative associations with IQ. PBDEs are increasingly being replaced by OPFRs, which have already raised concerns, with two studies showing decreases in IQ related to prenatal exposure.
> Prenatal exposure and autism spectrum disorder
Studies of prenatal EDC exposure and clinical outcomes such as attention deficit disorder and autism spectrum disorder have been limited in part by the rarity of these conditions. For autism spectrum disorder, the strongest evidence exists for a relationship with organophosphate pesticides.
Studies from California, New York State, and Cincinnati (USA) have reported an association between exposure to organophosphate pesticides and an increased risk of autism spectrum disorder or increased scores on the Social Responsiveness Scale , a questionnaire for parents used to evaluate signs of autism spectrum disorder.
Three studies of pyrethroids have suggested an increased risk of autism spectrum disorder in children living near areas with higher pyrethroid use estimated by pesticide registries. Studies of other EDCs have not provided much clarity regarding autism spectrum disorder.
> Prenatal exposure and child behavioral outcomes
Scales used to measure attention deficit disorder and related behavioral outcomes have shown more consistent evidence of association with prenatal exposure to EDCs than scales used for autism spectrum disorder. Adverse associations with prenatal PBDE exposure have been identified in several regions of the US.
Dutch and Spanish studies did not identify associations, although the difference in results could be explained by the higher prevalence of PBDE exposure in the US compared to Europe. A South Korean study reported an increase in children’s scores on scales for attention deficit disorder in mothers who had been exposed to higher concentrations of PBDEs, and a Norwegian study observed divergent associations with different PBDEs in milk maternal.
In utero exposure to organophosphate pesticides has been associated with higher scores on the Child Behavior Checklist in the US, supported by evidence in Mexican children, although a Danish longitudinal study did not identify any association.
Cohorts from France, the US, and Denmark reported that increases in scores for attention deficit hyperactivity disorder, internalizing symptoms (e.g., anxiety, depression, and somatization), and externalizing symptoms (e.g., aggression , hyperactivity and behavioral problems) were related to urinary pyrethroid concentrations.
Among 16 analyzes of relationships between prenatal BPA exposure and childhood behavior, 13 articles (representing seven different cohorts) reported detrimental associations.
Cohorts that have examined sex-specific associations with prenatal BPA exposure have observed increased externalizing behaviors or other behavioral effects in boys, while few studies have reported effects in girls. Overall, evidence for associations between OPFR and behavioral problems is sparse but consistent, while numerous studies of phthalates and behavior have reported varying results.
Obesity and metabolism
EDCs have been shown to interfere with peroxisome proliferator-activated factor receptors , estrogen receptors, and thyroid hormone receptors, among other metabolic signaling pathways, in prospective studies with in utero exposure measurements and in cross-sectional studies in adults. .
Furthermore, EDCs may produce a maladaptive thrifty phenotype, which increases cardiometabolic risk in adulthood.
The new data reinforce previous evidence of a link between prenatal BPA exposure and childhood obesity, and suggest associations of prenatal exposure to PFAS and phthalates with childhood adiposity. Evidence is mounting that exposure to PFAS and phthalates in adulthood may be associated with gestational diabetes, glucose intolerance, and obesity, and that these chemicals, as well as bisphenols, may be linked to type 2 diabetes.
> Prenatal exposure and childhood adiposity
Among the studies reviewed, prenatal PFAS exposure was associated with increases in childhood adiposity in multiple birth cohorts. Longer chain PFAS have increasingly been replaced in consumer products by shorter chain PFAS; A study in China suggests that short-chain PFAS are obesogenic and therefore a regrettable substitute.
A meta-analysis of ten cohort studies found an overall increase of 25% in overweight children and an increase of 0.10 units in BMI Z score per ng/ml of PFOA in maternal blood.
Compared with studies of prenatal PFAS exposure, studies of prenatal exposure to phthalates and bisphenols have not shown consistent associations with measures of childhood adiposity. The links for phthalates appear to be stronger in girls.
Two other studies identified associations between prenatal phthalate exposure and increased adiposity that did not appear to differ by sex. Few studies have examined the longitudinal effects of prenatal exposure to other chemicals on postnatal growth.
> Exposure in pregnancy and gestational diabetes
Six cohort studies and two case-control studies have raised compelling concerns about PFAS exposure during pregnancy, including short-chain replacements, contributing to gestational diabetes and glucose intolerance in pregnant women in several countries.
Four studies identified alterations in glucose tolerance, changes in glucose concentrations, or gestational diabetes associated with phthalate exposure during pregnancy, but a well-designed Canadian cohort study did not identify any association with gestational diabetes.
> Adult exposure and adult weight gain
Over the past 5 years, evidence has increased to suggest that phthalate exposure contributes to weight gain in adults, with the majority of studies conducted in women. One study examined exposures during pregnancy and identified possible divergent effects of different phthalates in relation to postpartum weight gain.
Two US studies have identified an association between weight gain and serum PFAS concentrations in both sexes. The POUNDS LOST trial follow-up of an energy-restricted diet provided mechanistic insights: PFAS, particularly perfluorooctane sulfonate (PFOS) and perfluorononanoic acid, were associated with reductions in resting metabolic rate.
In communities surrounding a chemical plant in the US that were continually exposed to high concentrations of PFAS, no association between PFAS exposure and weight gain in adults was reported.
> Adult exposure and type 2 diabetes
Occupational studies of persistent EDCs provided the first human evidence of diabetogenicity, when PFAS were identified as contributing to type 2 diabetes in a sample that was exposed to these chemicals.
Concentrations of total PFAS measured in blood samples have been associated with diabetes in Swedish and American cohorts. A dietary intervention appeared to modify the risk of diabetes associated with PFAS in a US study.
The strongest associations with diabetogenicity in adults relate to bisphenols and other non-persistent chemicals.
Case-control studies have associated BPA with an increased risk of diabetes. Two small-scale intervention studies (n < 25) have identified the effects of BPA on glucose, insulin, and C-peptide, suggesting that concentrations considered safe by US regulation alter the glucose-stimulated insulin response. in humans. A meta-analysis estimated the pooled relative risk of type 2 diabetes to be 1.45 (95% CI 1.13–1.87) for BPA and 1.48 (95% CI 0.98–2.25) for phthalates.
Since then, a French case cohort study identified a near doubling of type 2 diabetes risk in relation to BPA glucuronide and bisphenol S glucuronide (BPS), adding to concerns that BPS and other BPA replacements , which are widely used in aluminum cans and thermal paper receipts, can be regrettable substitutes.
Two case-control studies and two cohort studies have also identified exposure to phthalates as a risk factor for type 2 diabetes. Data have suggested that PBDEs, some non-persistent pesticides and herbicides, parabens, and benzophenones may be involved. associated with type 2 diabetes, but more research is needed in these areas.
Male reproductive health
Testicular dysgenesis syndrome is the predominant hypothesis linking prenatal EDC exposure to lifetime male reproductive health outcomes.
Testicular dysgenesis syndrome proposes that prenatal exposure to EDCs interferes with healthy testicular development, including the differentiation and proliferation of fetal germ cells that give rise to spermatogonia, the Sertoli cells that assist in the transformation of those spermatogonia to functional sperm and Leydig cells that produce the testosterone necessary for testicular descent and general masculinization.
Furthermore, evidence is accumulating of associations of occupational exposure to persistent pesticides with prostate cancer, and of exposure to bisphenols, PFAS, phthalates, and organophosphate pesticides with reduced semen quality.
> Prenatal and perinatal exposure and genital malformations
A large Canadian study that measured PBDEs in hair samples obtained from mothers 3 to 18 months postpartum reported a positive association with cryptorchidism. Evidence for associations of prenatal and perinatal exposure to numerous other persistent and nonpersistent chemicals with hypospadias and cryptorchidism was scarce or inconsistent.
> Testicular cancer
Although much remains to be understood about the environmental origins of testicular cancer, a condition that has increased in many countries since the mid-20th century, no new biomarker studies have been published since 2015. The few studies published since 2015 were either ecological studies or They relied on records of pesticide use and examined exposure only to PFAS and pesticides.
> Prostate cancer
Overall, occupational exposure to pesticides was consistently associated with prostate cancer in the United States. Only one study, from the Netherlands, reported an inverse relationship with self-reported occupational pesticide use, while another study from Australia found no significant association.
Results for self-reported exposure to non-persistent pesticides were less consistent, and results were sparse for other chemicals, including phthalates, BPA, PBDEs, polycyclic aromatic hydrocarbons (PAHs), and PFAS.
> Testosterone
The theory of testicular dysgenesis syndrome postulates that prenatal exposure to EDC impairs the proliferation and development of fetal Leydig cells, leading to reduced testosterone production throughout life.
Most evidence from cross-sectional studies of boys and men across the life course supports a negative association of DEHP or its major metabolite MEHP, or both, with testosterone. Studies of prenatal exposure were less consistent.
Although two studies observed negative associations of DEHP or MEHP with free testosterone at birth and between ages 8 and 14 years, four studies found no associations with testosterone in adulthood. The Australian Raine Longitudinal Study reported a positive association between prenatal exposure to DEHP, MEHP, the substitutive chemical diisononyl phthalate, and monoisononyl phthalate (the major metabolite of diisononyl phthalate) with total testosterone at ages 20 to 22 years. However, phthalates were measured in stored maternal serum in this study, which is less reliable than urine measurements.
> Semen quality
Most studies on semen quality are cross-sectional and do not contain information on in utero and early life exposure, so they cannot provide evidence to support the testicular dysgenesis syndrome hypothesis. The results of these studies remain relevant to the question of how EDCs affect sperm production, which occurs continuously starting at puberty and affects male fertility.
Most studies investigating phthalates reported negative associations with at least one, but often multiple semen quality parameters, including sperm concentration, motility, and morphology, with low- and high-molecular-weight phthalates being implicated.
Evidence is also increasing for a negative association between BPA and semen quality. A Boston-based study was the only one to look at BPS, a widely used BPA replacement that shares its obesogenic properties, and reported negative associations with sperm concentration, motility, and morphology, but only in overweight or obese men.
Three studies examining organophosphate pesticides and semen quality reported negative associations, as did four studies examining PFAS. The results were more variable for benzophenones, triclosan, parabens and PBDEs, and scarce for pyrethroids, carbamates and OPFR. Many of these studies recruited men who were part of couples seeking fertility treatment, so the results may not be generalizable.
female reproductive health
Parallel to the testicular dysgenesis syndrome hypothesis linking prenatal endocrine disruption to adverse male reproductive health outcomes, the ovarian dysgenesis syndrome hypothesis suggests that prenatal exposure to EDCs could lead to pathophysiological reproductive conditions in women, including polycystic ovary syndrome, endometriosis, uterine fibroids and cancer.
Few studies have had the data for prenatal exposure that would be necessary to test this hypothesis; however, there is substantial evidence to implicate EDC exposure in these diagnoses. In particular, studies identified an increased risk of polycystic ovary syndrome in association with exposure to BPA and PFAS; relationship between phthalates and endometriosis; and suggested associations of PFAS with endometriosis and of organophosphate pesticides and PFAS with breast cancer.
Similar to findings in male reproductive health, most epidemiological studies of female reproductive health are cross-sectional and cannot be interpreted to support causal associations, especially when participants had pre-existing conditions.
> Polycystic ovary syndrome
Among several studies examining associations between EDCs and PCOS, the evidence is strongest for an association with PFAS. Three cross-sectional studies of PCOS reported positive associations with several PFAS: a study in China with perfluorododecanoic acid, a US study with PFOA and PFOS, and a smaller study in the United Kingdom with PFOS alone.
Evidence is also accumulating for a link between BPA and polycystic ovary syndrome. Overall, knowledge about other EDCs, such as PBDEs, phthalates, PAHs, and triclosan, and PCOS is beginning to emerge, but conclusions cannot yet be drawn about these chemicals.
> Endometriosis and uterine fibroids
Notable additions have been made to the EDC and endometriosis literature regarding PFAS, but the results are inconsistent. An analysis of 2002-2006 data from the US NHANES and the ENDO study in 2007-2009 reported positive associations with PFOS, PFOA, and perfluorononanoic acid.
A 2017 Chinese study suggested a positive association with perfluorobutane sulfonate and negative associations with perfluoroheptanoic acid, perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid.
One cross-sectional study showed a positive association between serum DEHP and endometriosis and another study reported a positive association between urinary mono-2-ethyl-5-carboxypentyl phthalate (a metabolite of DEHP) and endometriosis. A third study of phthalates and endometriosis found no associations, although this study was smaller and did not adjust for covariates. Studies of EDC and uterine fibroids have focused on phthalates and phenols, but results have been mixed.
> Breast, endometrial and ovarian cancer
Several studies reported positive associations for PFAS and organophosphate pesticides. Evidence for PFAS includes results from the Child Health and Development Studies (US), in which prenatal exposure to N-ethyl-perfluorooctane sulfonamidoacetic acid, a precursor to PFOS, was positively associated with breast cancer in women. daughters, while prenatal exposure to PFOS was protective.
Other longitudinal analyzes include the French E3N study of women born between 1925 and 1950, which reported a positive association between PFOS and postmenopausal breast cancer, and the Danish National Birth Cohort study, in which perfluorooctane sulfonamide in first trimester blood samples was positively associated with the postnatal development of maternal breast cancer, while PFHxS was protective.
In a cross-sectional study of Greenland Inuit women, PFOS, PFHxS, and the sum of perfluoroalkyl acids were associated with increased odds of breast cancer. Finally, an ecological study in the Italian region of Veneto reported higher female breast cancer mortality rates in municipalities with PFAS-contaminated drinking water.
All four studies that examined exposure to organophosphate pesticides and breast cancer reported an increased risk. None of these studies measured chemicals in the blood or metabolites in the urine; all were studies of agricultural populations that estimated exposure from self-reports or geocoded addresses linked to pesticide records.
The literature on phthalates and breast cancer is scarce with inconsistent results. The results of the studies of PBDEs, phenols, benzophenones, parabens and carbamate and pyrethroid insecticides were scarce or not significant. Among the few articles published on EDC and other female reproductive cancers (e.g., endometrial and ovarian cancer), studies examined organophosphate pesticides, diazinon, and atrazine. However, there was not enough evidence to draw conclusions.
Discussion
This article suggests new adverse health effects from commonly used EDCs with probable causality and reinforces evidence from many other EDCs that have been previously identified by an expert panel commissioned by WHO and UNEP.
Growing evidence of these environmental contributors to non-communicable diseases suggests that synthetic chemicals are ignored or at least underestimated as a target of the 2030 Sustainable Development Goals (SDGs). The new exposure-outcome pairings proposed here have not been subject to systematic review methods or application of the GRADE system and other methods to evaluate the strength of the evidence.
By reviewing hundreds of published studies, the authors have emphasized the many challenges in unraveling the complex relationships of EDC exposure with diseases and disabilities across the lifespan. Some of these challenges can be addressed through technological advances and novel study designs.
In particular, given the high variability in concentrations of BPA and other non-persistent chemicals in individuals, prenatal studies that rely on a point biological sample during pregnancy or a given period of pregnancy (e.g., when evaluating associations with specific quarterly exposure) probably have a strong attenuation bias and low power.
Studies should aim to collect multiple biological samples throughout pregnancy to reduce measurement error. Another problem in human studies is the inability to easily measure chemicals in target tissues (e.g., ovary) and continued gaps in knowledge about the distribution and mobilization of chemicals during physiological events, such as pregnancy and menopause.
Many of the articles described limit their examination to a single class of chemical exposures or their metabolites. The composition of mixtures also varies from individual to individual, and the high cost of analytical technologies has generally restricted the necessary and simultaneous study of the thousands of natural and synthetic compounds with endocrine effects. Larger sample sizes are also needed to sufficiently power testing for interaction across chemical mixtures.
Intervention studies have produced rapid decreases in exposure to organophosphate pesticides, bisphenols, phthalates, parabens, and triclosans, but these studies have not examined changes in disease or intermediate markers. Randomized designs of interventions to increase or decrease exposure generally have little applicability due to ethical and logistical considerations.
A theme throughout the studies reviewed is the emergence of human health effects due to EDC replacements with poorly tested compounds. These health effects include the neurodevelopmental effects of pyrethroids, which are replacing organophosphate pesticides, and of OPFRs used as substitutes for their brominated counterparts; the metabolic effects of BPS and other BPA analogues, as well as short-chain PFAS and the reproductive effects of replacing diisononyl phthalate with DEHP.
The few studies of associations of these exposures with human health, many of which have identified adverse effects, support the conclusion that regulators should treat chemicals as classes rather than individual compounds and strengthen pre-release toxicological testing. commercialization.
More research will always be needed to more precisely elaborate the effects of EDCs and other synthetic chemicals on human health. As Bradford Hill described in his landmark lecture on causality, actions, in this case, to reduce exposure to EDCs, require consideration of the evidence and risks involved in the decision. In many cases, alternative manufacturing practices can be applied to mitigate exposure to EDCs.
Additional costs to society will need to be weighed against the economic benefits of reduced disease and disability, as well as other social effects (e.g., ecosystem effects). The last 5 years of research on EDC have highlighted the importance of what it entails for human health.
Although there are actions that individuals can take to reduce their exposure, the ultimate way to make a difference at the population level is through state regulation.
Regulation can eliminate environmental injustices when people are left to implement sometimes costly changes in their daily lives (e.g., buying organic foods).
