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Environment and Occupational Issues - Endocrine Active Chemicals (EACs)

Endocrine Primer

The Endocrine System

The endocrine system consists of glands or parts of glands whose secretions (called hormones) are distributed in the human body by means of the bloodstream.

The major organs of the endocrine system are the hypothalamus, the pituitary gland, the thyroid gland, the parathyroid glands, the islets of the pancreas, the adrenal glands, the testes, and the ovaries. During pregnancy, the placenta also acts as an endocrine gland in addition to its other functions.

To find out more about the endocrine system point your mouse to the glands in the image.

The endocrine system is composed of glands that produce hormones that released into the circulation for transport to target tissue sites of action remote to the site of production. Endocrine glands include the pineal, parts of the brain, pituitary, thyroid, pancreas, adrenal, and the gonads (ovaries and testis). In pregnant women the placenta also functions as an endocrine gland becoming the principle site of steroid production during pregnancy. The hormones produced by these glands may be either proteins or steroids such as the sex steroids: estrogen, progesterone and testosterone.

Humans have two systems of internal communication: the nervous system and the endocrine system. The endocrine system controls the delivery of messages through the release of chemicals known as hormones. Hormones are secreted directly into the blood by endocrine glands. Endocrine glands are found throughout the body and are responsible for releasing more than 50 hormones. Hormones control a number of essential functions in the body, including growth and development. For example, thyroxine, produced in the thyroid gland influences metabolic rate. Insulin and glucagon are produced in the pancreas and regulate glucose levels in the blood.

Basic Endocrinology

The endocrine system regulates many important functions in our bodies. The reproductive system, for example, depends on the actions of various hormones to produce eggs and sperm, maintain a pregnancy and to regulate the physical changes that accompany puberty and menopause.

Menstrual Cycle

The menstrual cycle involves a complex interplay of hormones and physiological responses over an approximate monthly period. The hormones involved include estrogen, luteinizing hormone (LH), follicular stimulating hormone (FSH), and progesterone.

FSH, a hormone secreted by the pituitary gland, stimulates the growth and maturation of the egg prior to its release from the ovary. This hormone promotes the development of the follicle, a shell of tissue that surrounds the egg. When the estrogen produced by the ovaries reaches its plateau, the hormone induces LH production by the pituitary gland which, in turn, triggers the release of the egg through the follicle. The egg then travels down the fallopian tube towards the uterus, or womb. After ovulation, the follicle breaks down into a yellow body, or "corpus luteum", and begins to produce progesterone. The progesterone halts the release of all other eggs until the following cycle and maintains the thick lining of the uterus in preparation for pregnancy. If the egg does become fertilized, it occurs in the fallopian tube within hours of ovulation. It is thought that the fertilized egg is then drawn toward the uterus via hairlike projections, called cilia, lining the fallopian tubes. Within approximately one week, the fertilized egg implants at the endometrium, the innermost layer of the uterus. On the other hand, if the egg is not fertilized as it moves down the fallopian tube, then progesterone production diminishes causing the endometrium to shed and pass through the vagina, a process called menstruation.

Most women begin menstruating between the ages of 8 and 18 years old, and stop menstruating between the ages of 40 and 60. The menstrual cycle lasts an average of 28 days and ovulation occurs on day 14 in most women. During their menstruation period, women can bleed anywhere from 3 to 7 days.


Osteoporosis is a disease characterized by reduced bone density and quality, leading to bone weakness and fragility and thus an increased risk of fractures, particularly of the hip, pelvis, wrist, and spine. Osteoporosis is often referred to as the "silent disease" because bone loss occurs gradually and without symptoms. The worldwide lifetime risk of incurring an osteoporotic fracture is 30-40% for women and approximately 13% for men. According to the World Health Organization (WHO), osteoporosis is second only to cardiovascular disease as a leading health problem. Women with premature menopause (age <45 years) and/or abnormal absence of menstrual periods (amenorrhoea) are at the greatest risk of developing osteoporosis. People with a family history of the disease, a low body mass index, and/or eating disorders are also more susceptible.

Many factors influence peak bone mass acquisition in both males and females, and endocrine factors are among the most prominent. Sex hormones, specifically estrogen and progesterone, appear to minimize the risk of osteoporotic fractures by reducing bone loss. Estrogen influences the rate of calcium absorption and deposition and thus controls bone remodeling. Estrogen deficiencies have been shown to accelerate bone turnover and resorption which can lead to osteoporosis. Because environmental contaminants have been shown to increase the activity of the liver enzymes that control the metabolism of estrogens and may thus alter circulating estrogen levels, there is concern that osteoporosis may be another adverse health outcome resulting from exposure to endocrine toxic chemicals.


Menopause refers to a gradual process that culminates with the cessation of a woman's regular monthly menstrual cycles and reproductive life. Menopause is a natural biological process that is characterized by hot flushes, irregular menstrual cycles, and reduced circulating estrogen and progesterone levels. The number of eggs remaining in the ovaries falls below a level threshold of approximately 1000, the ovaries stop producing these hormones completely and thus no longer release eggs. This most often occurs in women between the ages of 50 and 51, although some women experience menopause in their 30s, 40s, or even 60s. Premature menopause, referred to as premature ovarian failure (POF), occurs when a woman's periods stop before the age of 40 due to the cessation of estrogen production by the ovaries. POF may be caused by genetic abnormalities, viral infections, or production of autoantibodies which inhibit ovarian function. Certain medical procedures, such as chemotherapy and radiation therapy, can damage the ovaries and trigger menopause within a few months of treatment. Surgical removal of the ovaries (oophorectomy) will immediately induce menopause. Animal experiments have shown that many commercial chemicals are toxic to the ovaries and at high concentrations (levels beyond those measured in human tissues in contemporary studies) accelerate the loss of eggs from the ovaries. In contrast, cigarette smoking has been shown to accelerate the age of menopause and to result in the loss of eggs in animal studies. Therefore, there is concern that environmental toxicants can affect ovarian function, accelerate the rate of egg loss and lead to an advance in the age of menopause.

Estrogen and progesterone are female sex hormones that play key roles in uniquely female functions. In particular, these hormones are involved in preparing the female body for pregnancy by stimulating the growth of a thick lining in the uterus where a fertilized egg can grow and develop into a baby. Prior to menopause, the majority of estrogen and progesterone in a woman's body is produced by the ovaries. However, since other organs produce small amounts of these hormones (i.e. adrenal glands, liver, and kidneys), post-menopausal women continue to have low levels of estrogen and progesterone.


Spermatogenesis refers to the transformation of germ line stem cells into sperm cells within the seminiferous tubules of the testis. This process can be divided into three stages: proliferation, meiosis, and differentiation.

The seminiferous tubules are extensive structures within the testis and are lined by a stratified epithelium that consists of both germinal and somatic (Sertoli) cell types. Spermatogonia are stem cells of the first phase and are located along the basement membrane of the tubule. These cells proliferate by mitotic division and replenish the epithelium by continuously multiplying. In addition to this self-renewal process, the spermatogonia also produce stem cells that move away from the basement membrane towards the fluid-filled lumen of the seminiferous tubule through Sertoli cell junctions. These junctions make up the blood-testis barrier that separates the male sperm cells from the body.

The division of spermatogonia produces spermatocytes, cells of the second phase. Spermatocytes undergo reduction-division by meiosis, a process whereby a single germ cell increases its DNA content and then undergoes two successive nuclear divisions to produce four individual germ cells with half the number of chromosomes of the parent cell. The second meiotic division produces small, round cells known as spermatids that enter the final phase of spermatogenesis.

The immature, undifferentiated spermatid cells undergo spermiogenesis, an extended phase of cellular rearrangements that elongate and differentiate the spermatids into mature sperm. Spermiogenesis includes the following three major changes: (i) formation of the acrosomic system consisting of the hydrolytic enzymes required for sperm-egg interaction and fertilization; (ii) fusion of membranous organelles to the cell body plasma membrane; and (iii) formation of a long tail and loss of excess cytoplasm.

Spermatogenesis is regulated through endocrine interactions between the pituitary gland and Sertoli cells. This endocrine system is referred to as the brain-pituitary-gonad (BPG) axis and involves a series of signaling mechanisms that coordinate mammalian spermatogenesis. Two hormones, follicle-stimulating hormone (FSH) secreted by the pituitary, and androgens (i.e. testosterone) produced by the Leydig (interstitial) cells in the testis, control the functions of the Sertoli cell functions. FSH causes Sertoli cells to secrete androgen-binding protein, and this protein may facilitate germ cell differentiation by binding to androgens. A feedback-inhibition mechanism exists between luteinizing hormone (LH), another pituitary hormone, and the male sex hormones; LH controls androgen production and circulating androgen, in turn, causes a reduction in the production of LH. Although it is understood that FSH and androgens are required for sperm production, the target genes in Sertoli cells that are required for spermatogenesis to occur have not yet been identified.


A hormone is a chemical produced in the body that interacts with a receptor in a target tissue to cause a change in the function of that tissue. There are various types of hormones in the body and include the exocrine (glands with ducts that release hormones for local action), and endocrine hormones.

Hormones control a number of essential functions in the body, including growth and development. For example, thyroxine, produced in the thyroid gland influences metabolic rate. Insulin and glucagon are produced in the pancreas and regulate glucose levels in the blood.

Of the endocrine hormones we have learned that there are those that follow the classical pattern of being released into the circulation to induce effects at distant target sites. An example of a classical endocrine hormone would be growth hormone (GH) that is produced by the pituitary gland, released into the general circulation and transported throughout the body to cause tissues to grow.

We now realize that there are also hormones produced in endocrine glands that are released into the circulation to signal to other cells in the originating gland how to behave. These hormones are called paracrine hormones. Still others act directly on the cells that produced the hormone and are called apocrine hormones. In all cases endocrine hormones function as signaling molecules in a manner parallel to the nervous system. Whereas the nervous system functions to communicate quickly, the endocrine system employs hormones to tell cells and tissues throughout the body how to behave over more prolonged periods of time. Examples include development or regulation of the menstrual cycle in women or the production of sperm in men.

Protein hormones bind with receptors on the surface of cells. Interaction with cell surface receptors triggers a cascade of post receptor chemical reactions that ultimately result in interaction with the genetic machinery of the cell to stimulate the appropriate response.    

Steroid hormones are small molecules that are fat-soluble and thus easily diffuse through cell walls to bind with receptors inside of cells. Once bound with cells these receptors then form complexes, which enter the cell nucleus where the complex then binds with the genetic machinery of the cell to stimulate a response in the cell. These interactions a tremendously complex involving in some cases slightly different receptors of the same family as in the case of the estrogen receptor and the cooperation of coactivator and repressor molecules. Complicating the process even further is the recognition that some growth factors such as epidermal growth factor interact with the same genetic regions as the steroid receptor complex to stimulate the same response. Therefore, it is possible that a chemical can interact like a steroid without having any functional similarity to the hormone


Hormone Action


Estrogens are steroid hormones that are primarily synthesized in the ovary and testis and to a lesser extent, in peripheral tissues. The three forms of endogenous estrogens are estradiol, estrone, and estriol. Estrogens have biological effects on mammalian tissues that are essential for many physiological processes to occur. Although estrogens have been traditionally connected with female reproduction, the importance of these hormones in the male reproductive system and non-reproductive processes such as cardiovascular health and bone formation has also been established. In addition, the gastrointestinal tract and the immune system are now considered to be among the "estrogen targets".

Estrogen receptor (ER) molecules are members of the nuclear receptor superfamily, a group made up of ligand-inducible transcription factors that are activated by small lipophilic molecules (i.e. estrogens). Two distinct estrogen receptor molecules exist: the ERa and ERß. Although these receptors share a similar domain structure, they have different localizations and concentrations within the body. Both ER molecules consist of several subdivisions: a growth factor binding domain (AF-1), a ligand-binding domain (AF-2), and a DNA-binding domain (DBD) that binds at estrogen response elements on the chromosome. When complexed with estrogen, the ERa and ERß signal in opposite ways; estrogen appears to inhibit gene transcription when bound to ERß whereas transcription is activated when estrogen is bound to ERa.

Technological advances have allowed for the production of in vitro and transgenic animal models for the purpose of studying the physiological roles of ERa and ERß. In mice with disrupted ERa (aERKO), ERß (ßERKO), or both ERa and ERß, the most significant effects are observed in the reproductive systems of these animals. In particular, male and female aERKO are completely infertile, whereas the ßERKO males are fertile and the fertility of ßERKO females is decreased. Within the female reproductive system, estrogen withdrawal prevents the down-regulation of luteinizing hormone ß (LHß) gene transcription thus increasing serum LH concentrations and disrupting the regulation of gonadotropin production. With respect to male reproduction, both sperm deficiency and dilation of the seminiferous tubules have been observed in aERKO males.

Decreasing estrogen production may also have adverse effects on the cardiovascular system. The vascular cells in postmenopausal women tend to proliferate at a faster rate than those in pre-menopausal women, and this is though to increase the risk of developing atherosclerosis, a vascular disease in which blood vessels become blocked due to plaque build-up. Estrogen may exert a cardio-protective role by inhibiting this cell proliferation in the vascular system.

Lack of estrogen may also accelerate bone loss in postmenopausal women which can lead to the development of osteoporosis. Bone remodeling, the process whereby new bone is formed and existing bone is removed (resorption), is affected by changes in estrogen production. Under normal conditions, osteoclast cells make resorption possible by continuously removing microscopic portions of bone and osteoblast cells fill in the holes by producing new bone. However, estrogen loss enhances the efficiency of osteoclasts leading to a more rapid rate of bone loss than bone formation, and thus more fragile bones.


Thyroid Hormone

The hypothalamus secretes thyroptophin-releasing hormone (TRH), which stimulates the production of thyroid-stimulating hormone (TSH) from the anterior pituitary gland. In turn, TSH stimulates thyroid hormone synthesis and secretion from the thyroid gland. High serum concentrations of thyroid hormones inhibit TRH and TSH secretion in a classical negative feedback loop. The two principle thyroid hormones, thyroxine (T4) and triiodotyronine (T3), are vital for cell metabolism, normal growth and development. Thyroid hormones also exert significant effects on the cardiovascular system, reproductive system, and central nervous system.

Thyroid hormones enter cells via diffusion through cell membranes and bind to specific receptors within the nucleus. Gene transcription is activated when the hormone-receptor complex interacts with the DNA of responsive genes. The many physiologic processes affected by thyroid hormones occur via thyroid hormone receptors. These receptors are members of a large super-family of nuclear receptors that modulate gene expression by functioning as hormonally-activated transcription factors. Thyroid hormone receptors encapsulate three functional domains: a ligand-binding domain, a DNA-binding domain, and a transactivation domain that forms complexes with other transcription factors to either activate or repress transcription. The four currently recognized mammalian thyroid hormone receptors are alpha-1, alpha-2, beta-1, and beta-2, and patterns of expression among these different forms vary by tissue and by developmental stage.

Thyroid hormones have profound effects on lipid and carbohydrate metabolism. Thyroid hormones increase basal metabolic rate by stimulating the metabolic activities within most tissues. Increased body heat production is one consequence of this activity. The levels of thyroid hormone are inversely correlated with triglyceride and cholesterol concentrations in plasma. In particular, fat mobilization is stimulated by increased levels of thyroid hormone which leads to increased plasma concentrations of fatty acids. In many tissues, thyroid hormones also promote the oxidation of fatty acids. With respect to carbohydrate metabolism, thyroid hormones increase the biosynthesis of new glucose and stimulate glucose entry into cells.

In addition to regulating metabolism, thyroid hormones also have direct effects on muscle growth and bone development. Thyroid hormones sustain normal muscle growth by controlling the rates of protein synthesis and degradation. Excessive thyroid hormone secretion diminishes protein synthesis and increases protein degradation, resulting in a catabolic state. The growth-promoting effect of thyroid hormone in bone and developing cartilage is coupled with that of growth hormone, a clear indication that multiple endocrine controls are involved.

Although the mechanisms by which thyroid hormone mediates fetal and neonatal brain development are not well understood, it is well accepted that thyroid hormone is essential to normal brain development. Significant changes in mammalian thyroid function take place during pregnancy. The rise in estrogen levels induces a dramatic increase in the transport protein T4-binding globulin (TBG). Elevated TBG synthesis leads to lower T4 concentrations, which elevates TSH secretion by the pituitary gland. The net effect is an increased demand on the thyroid gland and thus enhanced production and secretion of T3 and T4. Recent studies have demonstrated that any impairment in maternal thyroid function during fetal development can potentially interfere with normal fetal development. Several environmental contaminants have been shown in animal studies to displace thyroxine from serum carrier proteins and increase thyroid hormone metabolism resulting in a hypothyroid state. Therefore, there is concern that exposure to environmental contaminants could also affect human thyroid function although at present there are no epidemiological studies that provide overwhelming evidence of such an occurrence in the human population.



Testosterone is an androgenic hormone that promotes the normal development and maintenance of male sex and reproductive organs. Testosterone levels (i) facilitate spermatogenesis and promote the maturation of sperm, (ii) influence sexual desire and related behaviours, (iii) stimulate metabolic processes such as protein synthesis and muscle growth, (iv) facilitate the development of male secondary sexual characteristics such as bone mass, musculature, fat distribution, and hair patterns, and (v) aid in the maintenance of the male reproductive tract.

Testosterone production is regulated by a complex chain of signals referred to as the hypothalamic-pituitary-gonadal axis. Gonadotropin-releasing hormone (GnRH) is secreted by the hypothalamus in pulses and travels to the anterior pituitary via the hypophyseal portal system. The anterior pituitary gland then releases leutenizing hormone (LH) which in turn stimulates the production of testosterone by the interstitial Leydig cells in the testes. A negative-feedback loop controls the level of testosterone production - above-normal levels of testosterone in the circulation inhibits GnRH secretion by the hypothalamus which causes a reduction in LH secretion and lowers testosterone levels.

Testosterone is transported in plasma while bound to one of two types of plasma proteins: (i) sex hormone-binding globulin (SHBG) transports roughly two-thirds of circulating testosterone, and (ii) albumins bind the remaining one-third save for a very small percentage (< 2%) that remains free in the circulation to bind with androgen receptors. As a steroid, testosterone enters target cells by diffusing across cell membranes and binds to an intracellular receptor. The hormone-receptor complex then binds to DNA and promotes gene transcription. In some target cells, testosterone is converted into dihydrotestosterone (DHT) which can bind to the same receptors targeted by testosterone. Certain tissues, including those of the external genitalia and the prostate gland, are more responsive to DHT than to testosterone.

Testosterone production increases markedly at puberty and declines naturally after age 50. Insufficient testosterone production and secretion may result from damage or disease of the hypothalamus, pituitary, or testicles and can lead to developmental abnormalities of muscle, bone, and genitalia. Testosterone deficiency in males has been linked to cryptorchidism (failure of testicles to descend into scrotum), hypogonadism (enlargement of breast tissue), erectile dysfunction, diminished libido, depression, and osteoporosis. Recent studies have shown that some environmental chemicals act like anti-androgens by binding with the androgen receptor and blocking testosterone and DHT from binding and exerting their effects.



Cortisol is a steroid hormone that is released in the body in response to physical or psychological stress. The secretion of cortisol induces energy-directing processes for the purpose of providing the brain with sufficient energy sources that prepare an individual to deal with stressors. In addition to its role as a so-called "stress hormone", cortisol plays many key roles in almost every physiologic system. Regulation of blood pressure, cardiovascular function, carbohydrate metabolism, and immune function are among the best known functions of cortisol.

The secretion of cortisol into the bloodstream is regulated by a sensitive feedback system. Adrenocorticotropic hormone (ACTH) is synthesized and secreted by the pituitary gland and stimulates the production of cortisol from the adrenal glands. Secretion of ACTH is regulated by corticotropin-releasing factor (CRF), a hormone released by the hypothalamus. A negative feedback system signals the pituitary gland and hypothalamus to reduce ACTH and CRF output when adequate cortisol levels are present. The production of cortisol displays a circadian rhythm - concentrations of cortisol fluctuate throughout the day with high levels in the morning and low levels in the evening.

In plasma, the majority of cortisol circulates bound to corticosteroid-binding globulin (transcortin). Cortisol binds to specific glucocorticoid receptors in the cytoplasm and the hormone-receptor complex then moves into the nucleus where it binds to specific DNA response elements thereby modulating gene transcription and ultimately affecting numerous physiologic systems. In particular, cortisol stimulates numerous processes involved in increasing and maintaining normal blood glucose levels. In the presence of cortisol, muscle protein breaks down and amino acids are released into circulation. The liver utilizes these amino acids to synthesize glucose. Cortisol also provides the muscles with energy by inducing the release of fatty acids from fat cells and conserves glucose by inhibiting glucose uptake in muscle and adipose tissue.

The adrenal gland is a potential target for environmental toxicants. For example, some chemicals such as DDE have been shown to accumulate in cells of the adrenal context and to adversely affect cortisol production. While more is known about the effects of environmental chemicals in fish adrenal physiology very little is known about their effects in mammals. Indeed, the effects of environmental chemicals on adrenal function have not been widely studied.


List of Hormones

Endocrine hormones may be either proteins or steroids. Some of the main hormones, their common abbreviation, and the endocrine glands that produce them are listed in the following table together with the main function for these hormones.

Endocrine gland



Main function(s)




Biological clock


Antidiuretic hormone


Acts on the kidney to preserve fluid and electrolyte balance




Precursor hormone for ACTH and MSH


Luteinizing hormone


In females this LH acts on the ovary to stimulate the production of estrogens and induce ovulation. In males this LH acts on the testis to stimulate the production of testosterone.

Follicle Stimulating hormone


In females FSH stimulates the maturation of ovarian follicles. In males FSH acts on Sertoli cells and participates in the regulation of sperm production.


Adrenocorticotrophic hormone


ACTH acts on the adrenal gland to stimulate the production of cortisol.


Growth Hormone


GH acts of various tissues to stimulate the growth.




Milk let down during lactation


Melanocyte stimulating hormone


Stimulates skin tone


Thyroid stimulating hormone


TSH acts on the thyroid gland to signal the production of thyroxin




Regulates blood sugar levels.


Triiodothyronine and thyroxine

T3 and T4

Development of the brain and reproductive tract, and regulation of metabolism




Immune suppression and stress response




Estrogens (estradiol, estrone, estriol)

E2, E1, E3

Growth promotion, maintain elasticity of connective tissues, preserve bone mass and, vascular compliance



Maintain endometrium in preparation for pregnancy




Precursor for estrogen and acts on libido.




Feedback regulation on pituitary FSH secretion




Growth of male secondary sexual characteristics, sperm production and libido



Some male secondary sexual characteristics.




Feedback regulation on pituitary FSH secretion




Maintenance of pregnancy




Endocrine Disruption

There are a number of terms that have been applied to the chemicals in the environment that are believed to affect the endocrine system. These include endocrine disrupters, hormonally active agents, environmental estrogens and endocrine modulating substances.

An endocrine disruptor has been defined as "as an exogenous agent that interferes with the synthesis, secretion, transport, binding, action or elimination of natural hormones in the body that is responsible for the maintenance of homeostasis, reproduction, development and/or behaviour" (USEPA 1997). It is also described as an "exogenous substance that causes adverse health effects in an intact organism or its progeny, subsequent to changes in endocrine function (EC 1997).

"Endocrine disruption" refers to the fact that there is negative interference or permanent adverse consequences beyond the range of everyday fluctuations of hormone levels.

There is considerable controversy surrounding the use of these terms. For instance, some scientists disagree with the use of the term "disrupter". They argue that these chemicals may either over or under modulate the activity of a particular hormone and not necessary "disrupt" the endocrine system. Furthermore, the human health consequences of these chemicals are still not clearly understood. The academic community, government and the media has predominantly used the term "endocrine disrupting chemicals".

The group of hormones believed to be most susceptible to the action of endocrine active chemicals is steroids. Steroid hormones are produced in the gonads; namely the testes of males and the ovaries of females. The male steroids are termed androgens, the main one being testosterone. Androgens that are produced early in the development of an embryo will direct its development as a male. At puberty, high concentrations of androgens are responsible for the development of human male secondary sexual characteristics such as male patterns of hair growth and deepening voice. The female steroids are estrogens and progestins. The main estrogenic chemical is estradiol while the predominant progestin is progesterone. During puberty, as the ovaries mature, the levels of estrogens and progestins increase. This leads to the initiation of the menstrual cycle, breast development and increases in uterine tissue, broadening of the pelvis and increases in the levels of subcutaneous fat.


What is an Endocrine Active Chemical?

Within the last decade the terms endocrine active chemical, endocrine modulator and hormone mimics have entered the lay and scientific jargon as terms to describe exogenous chemicals that alter the function(s) of the endocrine system and consequently cause adverse health effects in an organism, its progeny or subpopulations. However, these terms have been difficult to define, leading to different definitions in the literature, considerable controversy, and more importantly confusion within the scientific and lay communities about what is and what is not an endocrine disrupter. We therefore put forward the term endocrine toxicant as an alternative that may be more appropriate for several reasons.

For the term endocrine active chemical and its attendant definition to be useful it must allow us to separate chemicals into those that cause changes in hormone function and those that do not. This definition hinges on two key points: altered endocrine homeostasis and induction of an adverse health effect.

The endocrine system is a communication system that maintains normal physiological balance across multiple organ systems. It accomplishes this by modulating or regulating the activity of almost every body system in reaction to variations in body temperature, activity level, stress, and circulating levels of nutrients and hormones required for growth, reproduction, and metabolism. Hence, any exogenous chemical, no matter how innocuous, may disrupt the physiological balance of the body either by direct interaction with hormone receptors or indirectly through changes induced in other organ systems. For example, consuming food causes changes in numerous hormones involved in digestion and metabolism. It is also recognized that bright light will alter hormone levels in the brain affecting human behavior and depression. Thus, even foods and light could be considered as endocrine disrupters since they do induce functional changes in hormone levels. Hence, use of the terms disrupter, modulator or mimic does little to help us distinguish between chemicals that do or do not adversely alter endocrine homeostasis.

In screening chemicals for potential adverse health effects, some argue that it should be enough to show that exposure to a chemical alters the endocrine system to a measurable degree because even slight alterations in endocrine balance may be sufficient to induce adverse health effects in sensitive populations. While this is an important issue, it is not unique to chemicals that cause endocrine toxicity. Many toxicants, depending on level of exposure, will induce measurable changes in gene expression and in some cases circulating hormone levels that are within normal limits. Therefore, coupling the affected system (endocrine) with an adverse health effect will help discriminate between hazardous and non-hazardous endocrine disrupters - we suggest this is best accomplished by the term endocrine toxicant.

The term endocrine active chemical is widely used at present by representatives from the media, regulatory groups, academic scientists, and non-governmental organizations to communicate divergent meanings. The net result is significant confusion surrounding the messages that are being communicated concerning the potential for chemicals to interact with physiological systems and to induce endocrine toxicity. We therefore prefer the use of the term endocrine toxicants to describe chemicals that disrupt endocrine homeostasis and induce adverse health effects. This term clearly communicates that a chemical has been shown to be toxic through an endocrine mechanism and thus enables us to discriminate between chemicals with this property and those without.


Sources of Endocrine Active Chemicals

Endocrine active chemicals are generally defined as exogenous substances that alter the function(s) of the endocrine system and consequently cause adverse health effects in an organism, its progeny or subpopulations. Endocrine active chemicals include natural and synthetic hormones, phytoestrogens, pesticides and a variety of industrial chemicals and by-products. This enormous diversity means that it is not possible to define a 'typical' endocrine active chemical. Classification is further complicated by the often inconsistent data, poorly defined mechanism(s) of action, lack of exposure data in both animal and human populations. The so-called "endocrine active chemicals" (EACs) possess a wide range of biophysical characteristics; some are lipophilic and persistent while others are hydrophilic and rapidly degraded. Some adverse health effects have been linked to complex mixtures of chemical compounds, making the identification of the hormonally active components extremely difficult. General sources of endocrine disruption are described here and include ingestion of food, medications, pesticides and industrial chemicals. While there are a vast number of chemicals used in industry it is important to note that there is a broad range of toxic profiles ranging from non-toxic to very toxic. The effect of exposure on the endocrine system is not known for the majority of chemicals in use today. Moreover, the effect of chemical exposure on our physiology remains uncertain and thus toxicity testing must be considered a priority. Only through rigorous testing can the toxic characteristics and mechanisms of action of chemicals regardless of source (man-made or dietary) be determined and evidence based regulatory decisions taken to protect human health and human enterprises that are integral to our quality of life.

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Endocrine Disruption in Humans


Susceptible Populations

Endocrine systems of the body are responsible for regulating many intricate physiological processes. Substances which interact with the endocrine system can potentially have profound effects on health. Whether or not there are health effects may depend on the gender and stage of development of the individual and the dose and potency of the substance.


Fetal Development

Fetal development may represent a period of increased sensitivity to chemical insult due to the dynamic processes of growth and maturation which occur during this time. The different stages of development of the fetus are referred to as critical windows of development and include; cell proliferation in developing organs; cell migration; and development of specialized function. Disruptions to the intricate hormonal regulation of these processes can result in long-term irreversible programming changes which may lead to the occurrence of disease, such as cancer, later in life. If there is chemical insult at sufficient dosage during these sensitive windows of development, irreversible organizational effects can occur which may lead to effects on sexual differentiation, as well as on the maturing immune system and neuro-endocrine system. To date, there are no known cause and effect outcomes affecting human fetal development that scientists agree have come from low level, environmentally relevant exposures to endocrine active compounds but there are several proven relationships in experimental animals.



Children may also be vulnerable to the effects of chemical exposures. There are a number of differences in physiological and metabolic processes between children and adults that can influence exposure and response. Differences in absorption rates, distribution patterns and some metabolic pathways in pediatric populations can influence the effective dose of a compound, subsequently determining its toxicity and effects.

These differences arise as a result of maturing organ systems which have not yet developed to full capacity, as well as other physiological differences which influence the movement of the chemical throughout the body. In addition there are important differences in exposure circumstances between adults and children. Compared to adults, children ingest more food, drink more water, and breathe more air per pound of body weight.       

Behavioral practices of young children, including play close to the ground, increase the likelihood of exposure to contaminants in dust and soil. Children also frequently engage in hand-to-mouth behaviour, and are likely to put objects which have come into contact with the ground (such as toys) into their mouths. Breast-milk constitutes an additional unique route of exposure for children. Endocrine active compounds derived from the diet can accumulate in fat stores and are subsequently secreted in breast milk. If there is chemical insult at sufficient dosage during childhood to an endocrine active substance with sufficient potency, adverse effects could occur that influence growth patterns, neurodevelopment, and puberty. To date, there are no known cause and effect outcomes in children that scientists agree have come from low level, environmentally relevant exposures to endocrine active compounds but there are several proven relationships in experimental animals.



Individuals in their fertile years comprise another potential susceptible subpopulation, both males and females are vulnerable to impairment of reproductive function following exposure to endocrine active compounds, if the exposure is of a sufficient magnitude and the substance is of sufficient potency.



The menstrual cycle is highly regulated through the interactions of several hormones and physiological responses. Interference of these hormonal signals can lead to abnormalities in the growth and development of the egg prior to its release from the ovary, or failure of the egg to be released from the follicle. These changes in the normal process of ovulation can lead to infertility. Disruption of the hormonal regulation of the menstrual cycle has also been associated with the development of endometriosis. The contraceptive pill acts through the hormone system of females, and is in a sense a form of endocrine disruption. In terms of adverse effects in females, the overall weight of the scientific evidence does not support a connection between exposures to low level, environmentally relevant doses of endocrine active compounds and breast cancer, endometrial cancer or ovarian cancer. However, there has been little epidemiologic research of adequate quality on this issue and the potential for effects of low-level environmental contaminants remains an important research issue.



Males are also at risk of developing reproductive abnormalities due to the dynamic process of sperm production. Spermatogenesis involves a series of signaling mechanisms which is regulated through the brain-pituitary-gonad axis. Sperm is constantly being produced and therefore these developing cells are theoretically susceptible to endocrine disrupting events. If there is chemical insult at sufficient dosage to an endocrine active substance with sufficient potency, adverse effects could occur that influence sperm production, sperm motility or sperm morphology. In terms of adverse effects in males, the overall weight of the scientific evidence does not support a connection between exposures to low level, environmentally relevant doses of endocrine active compounds and changes in sperm count. Although some scientists have theorized that exposure to endocrine active compounds may be associated with increases in testicular cancer, a clear cause and effect relationship has not been established, and research continues to evaluate a wide range of potential risk factors.

Men and women who are occupational exposed to endocrine active compounds may be the subset of the adult population that experiences the highest degree of exposures. Some of the occupations which have been postulated to be associated with relatively higher exposures to potential endocrine active compounds include agricultural workers, workers in the plastics industry, painters, hairdressers, laboratory workers, textile workers and cleaners.    

In summary, endocrine active chemicals have the potential to cause a variety of adverse health effects. Lessons learned from birth defects resulting from exposures to DES, thalidomide, alcohol and cocaine demonstrate that the fetal period represents a critical window of development that is susceptible to environmental modulation. As with all cause and effect relationships, however, the dose of the chemical, duration and timing of exposure and the biological plausibility of the mechanism of action are important factors in assessing a relationship between chemical exposure and adverse health outcome. To date, the overall weight of the scientific evidence does not support a connection between exposures to low level, environmentally relevant doses of endocrine active compounds and adverse effects in humans. On a theoretical basis, the type and severity of effects would be dependent on the specific timing of exposure relative to the developmental stage of the individual, gender and the dose and potency of the substance.


Critical Windows of Human Exposure

Different periods of human development are susceptible to chemical exposure. These 'critical windows' are characterized by hormone regulation of:

  1. cell proliferation in developing organs,
  2. cell migration, and
  3. development of specialized function


Identification of critical windows of chemical sensitivity is extremely important in the evaluation of the effects of all toxicant chemicals including those suspected of causing endocrine disruption. Fetal chemical exposure, for example, may result in permanent alterations in reproductive or neurological function. While fetal development is commonly known to be a period of increased sensitivity to chemical insult, childhood and adolescence are also marked by continued maturation of key endocrine systems, and are therefore susceptible to chemical exposure.



Endocrine Modulation in Nature

Animals are thought to serve as sentinel species for potential adverse health effects in humans. Therefore, to better understand the effects of environmental contaminants on our ecosystem, and to identify potential health risks to the human population, disease trends and changes in wildlife and fish population numbers have been studied. The effects of biohazardous chemical contaminants on wildlife have also been explored to identify the mechanisms through which these agents may exert their adverse effects. Consequently, key observations from wildlife and fish populations are included here.

Click on animal to learn more about endocrine modulation in nature.



Health Risks

Endocrine active chemicals (EACs) have been linked by some to a wide variety of adverse reproductive/developmental health risks in humans.

  1. Breast Cancer
  2. Endometrial Cancer
  3. Endometriosis
  4. Fecundity and Fertility
  5. Spontaneous Abortion
  6. Sex Ratios
  7. Testicular Cancer
  8. Ovarian Cancer
  9. Prostate Cancer
  10. Semen Quality
  11. Male Reproductive Tract Abnormalities
  12. Precocious Puberty
  13. Thyroid Hormones
  14. Immune System


Further Reading
Foster WG, Agzarian J. (2008) Toward less confusing terminology in endocrine disruptor research. Journal of Toxicology and Environmental Health B Critical Reviews 11(3-4):152-161.

Phillips KP, Foster WG, Leiss W, Sahni V, Karyakina N, Turner MC, Kacew S, Krewski D. (2008) Assessing and managing risks arising from exposure to endocrine-active chemicals. Journal of Toxicology and Environmental Health B Critical Reviews 11(3-4):351-372.

Phillips KP, Foster WG. (2008) Key developments in endocrine disrupter research and human health. Journal of Toxicology and Environmental Health B Critical Reviews 11(3-4):322-344.


1. Breast Cancer

Health Risk
Exposure to environmental chemicals is thought to play a role in the development of breast cancer and explain the alarming increase in the incidence of breast cancer. Although a number of genes such as BRCA1 and BRCA2 have been associated with breast cancer, they account for a small percentage of all of the cases of documented breast cancer. Therefore other factors such as gene-environment interactions are thought to be involved in breast cancer initiation and promotion. Undiscovered breast cancer genes may also be important. Regardless, it has been proposed that exposure to environmental factors have a prominent role in the etiology of breast cancer. The incidence rates of breast cancer have been shown to have increased since the 1940's. Increased rates during the 1980's were influenced by breast cancer screening programs. However a recent study suggests that the rates of breast cancer have leveled off since the early 1990s.

Data linking environmental exposures and breast cancer are equivocal. Several studies have reported an association between exposure to environmental contaminants that fall into the organochlorine class and include the DDT metabolite DDE. However other reports have failed to find a similar association. When all of the studies have been collected together and their data pooled for statistical re-analyses, there was no association between organochlorine exposure and breast cancer. Reasons for failure to find an association between exposure to selected environmental contaminants and breast cancer are numerous and include but are not limited to the following: a) there is a long latency period between exposure and tumor formation; b) there are no definitive biomarkers for the onset or progression of breast cancer potentially resulting in misclassification of study subjects; and c) often exposure data are weak or absent. Additional difficulties in identifying biomarkers of breast cancer arise as most studies attempting to identify genes involved in breast cancer have focused on exposures during adulthood even though it has been suggested that exposures in utero or during the pubertal transition to estrogenic compounds may increase breast cancer risk perhaps via altered gene and/or protein expression in the fetus, neonate, or during the pubertal transition. Other factors that may contribute to failure to find an association, if one is indeed present is the influence of race and age. Some studies have shown a correlation between exposure and breast cancer diagnosis in one racial group but not in another. It may also be necessary to focus future studies on breast cancer estrogen-receptor status and menopausal status as the differences in hormonal status between pre- and post-menopausal women may preclude including them in the same analyses.

Numerous animal studies have been conducted to examine the effect of man-made chemicals on mammary tumor formation. These studies have demonstrated that environmental contaminants like DDE can promote tumor formation. However, rodent models of breast cancer have either used chemical inducers of tumor formation (DMBA or MNU) or transgenic mice bearing human breast cancer related genes linked with mouse viral promoters that are estrogen regulated. Unfortunately these models are highly artificial and thus limit translation of the findings from these studies to the human population.

Estrogen exposure is a well-documented risk factor for breast cancer. Hence it is reasoned that any additional estrogenic exposure increases a woman's risk for developing breast cancer. However, it must also be considered that the human exposure to environmental contaminants is very low. Moreover, the estrogenic activity of environmental contaminants is significantly lower than endogenous estrogen. Thus it is biologically plausible that estrogenic contaminants may exert tumor promoting activity in women the potential harm to health is complicated by the finding that consumption of foods containing dietary estrogens appears to reduce the risk of breast cancer. Thus it is possible that not all estrogens necessarily behave exactly the same way and therefore may have different biological consequences.

Taken together evidence of a trend, animal data and evidence of a biologically plausible mechanism suggests that there may be an association between exposure to environmental contaminants and breast cancer. However, there are many gaps in the knowledge set that need to be addressed in order to either substantiate or invalidate this association.

Useful Links
Cornell University: Environmental Chemicals and Breast Cancer Risk

Endocrine Disruptors Impact Women’s Health

Health & Environment: Endocrine disruptors and breast cancer video

National Cancer Institute: Breast Cancer

Silent Spring: Breast Cancer and the Environment


Further Reading
Abdel-Rahman WM, Moustafa YM, Ahmed BO, Mostafa RM. (2012) Endocrine Disruptors and Breast Cancer Risk – Time to Consider the Environment. Asian Pacific Journal of Cancer Prevention 13(12):5937-5946.

Band PR, Le ND, Fang R, Deschamps M. (2002) Carcinogenic and endocrine disrupting effects of cigarette smoke and risk of breast cancer. Lancet 360(9339):1044-1049.

Brisken C. (2008) Endocrine Disruptors and Breast Cancer. Chimia 62(5):406–409.

Brody JG, Aschengrau A, McKelvey W, Rudel RA, Swartz CH, Kennedy T. (2004) Breast cancer risk and historical exposure to pesticides from wide-area applications assessed with GIS. Environmental Health Perspectives 112(8):889-897.

Brophy JT, Keith MM, Watterson A, Park R, Gilbertson M, Maticka-Tyndale E, Beck M, Abu-Zahra H, Schneider K, Reinhartz A, Dematteo R, Luginaah I. (2012) Breast cancer risk in relation to occupations with exposure to carcinogens and endocrine disruptors: a Canadian case-control study. Environmental Health 11:87-104.
Charlier C, Albert A, Herman P, Hamoir E, Gaspard U, Meurisse M, Plomteux G. Breast cancer and serum organochlorine residues. (2003) Relationship between serum organochlorines and breast cancer. Occupational and Environmental Medicine 60:348-351.

Doherty LF, Bromer JG, Zhou Y, Aldad TS, Taylor HS. (2010) In Utero Exposure to Diethylstilbestrol (DES) or Bisphenol-A (BPA) Increases EZH2 Expression in the Mammary Gland: An Epigenetic Mechanism Linking Endocrine Disruptors to Breast Cancer. Hormones and Cancer 1(3):146-155

Engel L.S., Hill D.A., Hoppin J.A., Lubin J.H., Lynch C.F., Pierce J., Samanic C., Sandler D.P., Blair A., Alavanja, M.C. (2005) Pesticide Use and Breast Cancer Risk Among Farmers’ Wives in the Agricultural Health Study. American Journal of Epidemiology 161: 121-135.

Fenton SE, Hamm JT, Birnbaum LS, Youngblood GL. (2002) Persistent abnormalities in the rat mammary gland following gestational and lactational exposure to 2,3,7,8 - tetrachlorodibenzo-p-dioxin (TCDD). Toxicological Sciences (67):63-74.

Hopenhayn-Rich C, Stump ML, Browning SR. (2001) Regional assessment of Atrazine exposure and incidence of breast and ovarian cancers in Kentucky. Browning Archives of Environmental Contamination and Toxicology. 42:127-136.

Laden F, Collman G, Iwamoto K, Alberg AJ, Berkowitz GS, Freudenheim JL, Hankinson SE, Helzlsouer KJ, Holford TR, Huang HY, Moysich KB, Tessari JD, Wolff MS, Zheng T, Hunter DJ. (2001) 1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene and polychlorinated biphenyls and breast cancer: combined analysis of five U.S. studies. Journal of the National Cancer Institute 93(10):768-776.

Lopez-Cervantes M, Torres-Sánchez L, Tobías A, López-Carrillo L. (2004) Dichlorodiphenyltrichloroethane Burden and Breast Cancer Risk: A Meta-analysis of the Epidemiologic Evidence. Environmental Health Perspectives:112(2):207-214.

Reynolds P, Hurley SE, Goldberg DE, Yerabati S, Gunier RB, Hertz A, Anton-Culver H, Bernstein L, Deapen D, Horn-Ross PL, Peel D, Pinder R, Ross RK, West D, Wright WE, Ziogas A. (2004) Residential proximity to agricultural pesticide use and incidence of breast cancer in the California Teachers cohort. Environmental Research 96: 206-218.

Salehi F, Turner MC, Phillips KP, Wigle DT, Krewski D, Aronson KJ. (2008) Review of the etiology of breast cancer with special attention to organochlorines as potential endocrine disruptors. Journal of Toxicology and Environmental Health B Critical Review 11(3-4): 276-300.

Soto AM, Brisken C, Schaeberle C, Sonnenschein C. (2013) Does Cancer Start in the Womb? Altered Mammary Gland Development and Predisposition to Breast Cancer due to in Utero Exposure to Endocrine Disruptors. Journal of Mammary Gland Biology and Neoplasia, DOI:10.1007/s10911-013-9293-5.

Woolcott CG, Aronson KJ, Hanna WM, SenGupta SK, McCready DR, Sterns EE, Miller AB. (2001) Organochlorines and breast cancer risk by receptor status, tumor size, and grade (Canada). Cancer Causes and Control, 12: 395-404.

Zhang Y., Piece Wise J., Holford T., Zie H., Boyle P., Hoar Zahm S., Rusiecki J., Zou K., Zhang B., Zhu Y., Owens P., and Zheng T. (2004) Serum Polychlorinated Biphenyls, Cytochrome P-450 1A1 Polymorphisms, and Risk of Breast Cancer in Connecticut Women. American Journal of Epidemiology, 160: 1177-1183.


2. Endometrial Cancer

Health Risk
Endogenous and exogenous estrogens are important in the development of endometrial cancers. Endometrial cancer usually occurs between the ages of 50 and 65 years, and is rare before the age of 40. Endometrial cancer is the most common malignant tumor of the female genital tract. Increasing evidence suggests that at least two different types of endometrial cancer exist. Type I tumors occur more frequently, are estrogen-dependent and are associated with postmenopausal hormone replacement therapy (HRT) and tamoxifen. Continued exposure to estrogens unopposed by progesterone is a known risk factor for endometrial cancer, as is excess body weight. In addition to the possible effect on the development and continuation of obesity, diet may exert effects on the endogenous hormonal milieu, thus influencing development of this cancer. This type of cancer appears to develop through a series of precursor lesions including simple, complex and atypical hyperplasia. They generally have a good prognosis. Endometrial cancer type II is estrogen-independent, occurs among elderly women, and have a poor prognosis. The concern that environmental organochlorine pollutants may cause cancer in humans is widespread and has been tested almost exclusively in epidemiological studies of breast cancer.

Endometrial cancer ranks fourth in terms of cancer occurrence and eighth in terms of age-adjusted mortality in women. In the most industrialized countries, annual incidence rates are about 10 per 100,000 women in UK, Spain, and France and 25 per 100,000 women in USA and Canada. In 1999, in the USA, there were about 37,400 new cases or about 6% of all incident cancers. The mortality rates for this cancer have declined about 60% since the 1950s. Although endometrial cancer incidence showed a marked increase in the early 1970s, followed by a reduction in the 1980s, and back to previous levels, but since the 1980 the incidence has remained steady.

Environmental pollutants such as dichlorodiphenyltrichloroethane (DDT) and polychlorinated biphenyls (PCBs) may increase breast cancer risk partially through estrogenic activity. The association between HRT and endometrial cancer is much stronger than that between HRT and breast cancer. Therefore, one might plausibly expect that any carcinogenicity of organochlorine compounds would be easier to detect in endometrial than breast cancer. Unfortunately, there are few epidemiologic studies on this subject. In a population-based case-control study in Sweden (Weiderpass et al., 2000), serum levels of 10 chlorinated pesticides and 10 PCB congeners were measured. There were no significant associations between pesticide or PCB levels and endometrial cancer risk. To date, only one study has addressed the association between organochlorine pesticides and PCBs and the risk of endometrial cancer, and the results were negative (Sturgeon et al., 1998).

The estrogenicity of pesticide and PCBs has been noted in some animal studies. In one study, p, p'-DDT, the active pesticide, was active on uterine enzyme activities, as well as an edematous response in deep and superficial endometrium of immature female Sprague Dawley rats. In another study, o, p'-DDT has been associated with effects on hormones and reproductive behavior that imply estrogenic potency of this compound. In ovariectomized rats, it caused estrogenic responses in the endometrium. Thus, according to animal studies, the DDT and PCBs class of compound can bind to estrogen receptors. In addition to the estrogenic effects of PCBs, several PCB congeners exhibit antiestrogenic activity in vitro and in vivo. However there was no evidence of an association between environmental toxicant exposure and endometrial cancer in all animal studies conducted.

Analysis of the incidence of endometrial cancer should be the most informative with respect to a hormonal active agent effects, because the lining of the uterus (endometrium) is an exquisitely sensitive tissue both to estrogenic and to antiestrogenic effects in women.  The hypothesis that human exposure to environmental agents with estrogenic activity may cause endometrial cancer is not supported by animal studies and the very few epidemiological studies conducted to date. Nevertheless, it cannot be conclusively rejected on the basis of available data.


Useful Links
American Cancer Society: What is Endometrial Cancer?

Geneva Foundation for Medical Education and Research: Endometrial Cancer

Mayo Clinic: Endometrial Cancer

National Cancer Institute: Endometrial Cancer

Women’s College Hospital (Canada): Endometrial Cancer


Further Reading
Caserta D, Maranghi L, Mantovani A, Marci R, Maranghi F, Moscarini M. (2008) Impact of endocrine disruptor chemicals in gynaecology. Human Reproduction Update 14(1):59-72.

Hardell L, van Bavel B, Lindström G, Björnfoth H, Orgum P, Carlberg M, Sörensen CS, Graflund M. (2004) Adipose tissue concentrations of p,p'-DDE and the risk for endometrial cancer. Gynecologic Oncology 95(3):706-11.

Hiroi H, Tsutsumi O, Takeuchi T, Momoeda M, Ikezuki Y, Okamura A, Yokota H, Taketani Y. (2004) Differences in serum bisphenol a concentrations in premenopausal normal women and women with endometrial hyperplasia. Endocrine Journal 51(6):595-600.

Sturgeon SR, Brock JW, Potischman N, Needham LL, Rothman N, Brinton LA, Hoover RN. (1998) Serum concentrations of organochlorine compounds and endometrial cancer risk (United States). Cancer Causes and Control 9(4):417-424.

Weiderpass E, Adami HO, Baron JA, Wicklund-Glynn A, Aune M, Atuma S, Persson I. (2000) Organochlorines and endometrial cancer risk. Cancer Epidemiology Biomarkers Prevention 9(5):487-93.


3. Endometriosis

Health Risk
Environmental chemicals may play a role in the development and progression of endometriosis. Endometriosis is an estrogen dependent disease in which cells that line the uterus (endometrial cells) begin to grow in the pelvis and abdomen, most commonly on the ovaries, the outer surface of the uterus, the intestines or the ligaments that support the uterus. It is estimated that this disease affects approximately 15 % of women of reproductive ages. Women with endometriosis experience pain on menstruation and intercourse, leading to time off work, medication and in many cases surgery. The cause of endometriosis remains undetermined.

There is very little known concerning changes in the frequency of this disease. For example, it is not known if there are more women with endometriosis today than in previous years. In addition, it is not known if women living in regions with high exposure to environmental chemicals are at greater risk for developing this disease.

A small number of hospital-based studies have been conducted, in which the association between endometriosis and exposure to polychlorinated biphenyls (PCBs) and dioxin (TCDD) have been investigated. While two studies have reported a positive association between exposure to these chemicals and endometriosis the other two studies were unable to find a relationship. Unfortunately the number of patients included in these studies was too small to generate convincing evidence either in support of or against an association between endometriosis and environmental chemicals.

In rhesus monkeys long term exposure to TCDD in the diet has been shown to be associated with an increased frequency and severity of spontaneous endometriosis. Analysis of the serum from these monkeys revealed an association between endometriosis and exposure to TCDD and PCBs that act through the same receptor as TCDD. However, a second rhesus monkey study with long-term exposure to a commercial PCB mixture failed to find any relationship between this mixture of chemicals and endometriosis. A third study involving Cynomolgus monkeys showed that dioxin treatment at low doses antagonized the growth of endometrial cells whereas higher doses increased the survival and growth of these cells. In both rats and mice environmental chemicals such as the pesticide methoxychlor as well as PCBs and TCDD have been shown to facilitate the survival and growth of endometrial cells. These studies show that estrogenic chemicals can act to promote the growth of endometrial cells placed in the abdomen of these animals. A recent study has demonstrated that TCDD can antagonize the growth inhibiting effects of progesterone on endometrial cells growing outside of the uterus.

While both the human and animal data are inconclusive, the animal data show that environmental chemicals can affect the growth of endometrial cells albeit at high concentrations compared to the levels measured in tissues of the general population. However, it is not known if these chemicals are acting like hormones or are antagonizing the effects of the body's hormones through non-endocrine mechanisms.

Taken together the data do not support a conclusion that environmental chemicals are playing a role in the development or progression of endometriosis. The evidence does support however a conclusion that environmental chemicals may play a role in the pathology of this disease.
Useful Links
Canadian Women's Health Network: Endometriosis: Diagnosis and Treatments

Endometriosis Association: Toxic Link to Endometriosis

Endometriosis Forum

Environmental Protection Agency (EPA): Persistent Organic Pollutants and Endometriosis Risk

Epidemiology - Endocrine Disruptors and Human Endometriosis

Mayo Clinic: Endometriosis

The Society of Obstetricians and Gynaecologists of Canada: Endometriosis

Women’s College Hospital (Canada): Endometriosis


Further Reading
Anger DL, Foster WG. (2008) The link between environmental toxicant exposure and endometriosis. Frontiers in Bioscience 13:1578-93.

Eskenazi B, Macarelli P, Warner M, Samuels S, Vercellini P, Olive D, Needham LL, Paterson DB, Brambilla P, Gavoni N, Casalni S, Panazza S, Turner W, Gerthoux PM. (2002) Serum dioxin concentrations and endometriosis: a cohort study in Seveso, Italy. Environmental Health Perspectives 110(7):629-634.

Fierens S., Mairesse H., Heilier J-F., De Burbure C., Focant J-F., Eppe G., De Pauw E., Bernard A. (2003) Dioxin/ polychlorinated biphenyl body burden, diabetes and endometriosis: findings in a population-based study in Belgium. Biomarkers 8(6):529-534.

Foster WG. (2008) Endocrine toxicants including 2,3,7,8-terachlorodibenzo-p-dioxin (TCDD) and dioxin-like chemicals and endometriosis: is there a link? Journal of Toxicology and Environmental Health B Critical Reviews 11(3-4):177-187.

Lebel G, Dodin S, Ayotte P, Marcoux S, Ferron LA, Dewailly E. (1998) Organochlorine exposure and the risk of endometriosis. Fertility and Sterility 69(2):221-228.

Parente Barbosa C, Bentes De Souza AM, Bianco B, Christofolini DM. (2011) The effect of hormones on endometriosis development. Minerva Ginecologica 63(4):375-386.

Pauwels A, Schepens PJC, Hooghe TD, Delbeke L, Brouwer L, Weyler J. (2001) The risk of endometriosis and exposure to dioxins and polychlorinated biphenyls: a case control study of infertile women. Human Reproduction 16(10):2050-2055.

Signorile PG, Spugnini EP, Citro G, Viceconte R, Vincenzi B, Baldi F, Baldi A. (2012) Endocrine disruptors in utero cause ovarian damages linked to endometriosis. Frontiers in Bioscience (Elite Ed) 4:1724-30.


4. Fecundity and Fertility

Health Risk
More people today are experiencing difficulty in becoming pregnant because of exposure to hormonally active substances. Because of the complexity of human reproduction, it is often difficult to determine whether or not there is an actual increase in age-specific infertility rates. Published trend data for human fecundity are sparse, however, in North America, infertility rates have remained stable while the demand for fertility services has increased most likely due to an increase in the number of women above 35 years of age and a tendency to delay childbearing until later in life. In Sweden, analysis of birth registries has shown that the population of subfertile women, defined as those who did not become pregnant after more than 1 year, has actually decreased from 12.7% in 1983 to 8.3% in 1993 in the general population. Regional differences may exist since it has been observed that the time to pregnancy was shorter among couples in Finland than in the UK.

"Time to pregnancy" is an effective tool for measuring the impact of exogenous agents that affect reproduction as studies have shown that it can clearly demonstrate a difference among nonsmokers and smokers. It measures the time taken for a couple to conceive following unprotected intercourse for all subjects in a population-based approach and does not require categorization of subjects into fertile and infertile groups. Differences in time to pregnancy have been found in a prospective study involving seven well-defined geographical areas in Europe. The highest fecundity was observed in southern Italy and northern Sweden, the lowest fecundity was in east Germany. The differences in time to pregnancy remained significant after adjustment for regional differences in body mass, smoking, frequency of intercourse and sexually transmitted disease. The longest time to pregnancy was observed in Paris and the shortest in Rome.
Another useful approach in addition to time to pregnancy is to review the total fecundity of a population of people with no predisposition for limitation of family size. For example, there has been a decreased age-specific fertility rate in the Hutterite population, a group in which reproductive practices are unlikely to have changed over time. These retrospective cohort studies revealed a decline in the total number of children born beginning with a cohort 1931 to 1935 and a continuing decline with subsequent birth cohorts. These data appear to indicate some form of extraneous factor, although there is no clear link to an endocrine disruptor hypothesis.

Occupational exposures are often cited as evidence of external impacts on fertility but a review of the published literature fails to reveal a clear pattern of effects. In one study, 281 women with a diagnosis of infertility were compared to 216 postpartum women for chemical exposures. Women with a history of working in the agricultural industry had an elevated risk of infertility. A recent study of the exposure of female wood workers exposed to formaldehyde demonstrated a highly significant effect on time to pregnancy including an apparent dose-related effect as those with higher exposures (i.e. no gloves), had a more severe effect.

Several epidemiological studies have been undertaken to study the fecundity and fertility of farmers exposed to pesticides. A retrospective study of 43 couples in the Netherlands whose male partner was a fruit grower included 91 pregnancies from 1978 to 1990. Exposure to pesticides was determined by self-reported data. An adverse effect of pesticide exposure was found, mainly apparent in highly exposed men who tried to conceive during the spraying season. The incidence of couples consulting a physician because of a fertility problem was also much greater in the high exposure group. The same Dutch group initiated an on-going case control study on occupational exposures and semen quality among couples consulting an infertility clinic. Among 899 men who delivered a semen sample, an association between impaired semen parameters and aromatic solvent exposure was observed but no association was found with pesticide exposure. However, in another study significantly decreased fertilization rates were observed for couples with male partners exposed to pesticides and enrolled in an in vitro fertilization program. Adjustment for paternal or maternal smoking habits, caffeine use, alcohol consumption or other occupational exposures had little effect on the observed association. In contrast, a retrospective study of 2,012 farm couples demonstrated no strong or consistent pattern of association of exposure to various classes of pesticides with time to pregnancy. Similarly a large study made in Denmark and France on exposure to pesticides and a control group of agricultural workers did not demonstrate any effect of pesticide exposure on time to pregnancy. There have also been controversial results associated with the consumption of sport fish, containing what both PCBs and mercury, by males on time to pregnancy in two major studies.

Several distinct lines of evidence provide support for the biological plausibility that hormonally active chemicals can alter fecundity. Environmental contaminants, some of which possess hormone like activity, have been detected in human ovarian follicular fluid and seminal plasma of subjects attending fertility clinics. In animal studies, treatments with increasing concentrations of test compounds have been shown to reduce litter size in rodents. In male rodents, test compounds have been shown to reduce daily sperm production, and alter sperm morphology and motility. From an assessment of reproductive function as assessed by regulatory style rodent studies, the most definitive outcome measures include semen quality and longer estrus cycles. However, an endocrine mechanism of action has not been conclusively demonstrated to be the causal route for these effects. Moreover the dose required to induce changes in rodent fertility are in excess of those measured in contemporary residue analyses of human tissues.

Tissue culture experiments have shown that hormonally active agents can alter steroidogenesis in granulosa and Leydig cells and alter sperm-egg interactions. Other studies have shown that test substances can also affect oocyte quality. However, translation of in vitro results to whole animals and then to humans remains problematic.

In summary, the relationship of changes in the time to pregnancy to endocrine disruption is highly speculative. Part of this is due to the complex array of issues that may alter normal human reproduction and result in a longer time to pregnancy.


Useful Links
Attain Fertility: Could endocrine disruptors like BPA be disrupting your fertility?

Childbirth: Endocrine disruptors


Endocrine disruptors: The new enemies of fertility

eIVF Network: Endocrine disruptors decrease fertility

Global IVF: Environmental Toxins and Fertility

Human fertility under attack: From research to action on phthalates and endocrine disruptors


Further Reading
Balabanič D, Rupnik M, Klemenčič AK. (2011) Negative impact of endocrine-disrupting compounds on human reproductive health. Reproduction, Fertility, and Development 23(3):403-416.

Caserta D, Bordi G, Ciardo F, Marci R, La Rocca C, Tait S, Bergamasco B, Stecca L, Mantovani A, Guerranti C, Fanello EL, Perra G, Borghini F, Focardi SE, Moscarini M. (2013) The influence of endocrine disruptors in a selected population of infertile women. Gynecological Endocrinology 29(5):444-447.

Chen, A. and Rogan, W.J. (2003) Nonmalarial infant deaths and DDT use for malaria control. Emerging Infectious Diseases 9(8):960-964.

Cohn BA, Cirillo PM, Wolff MS, Schwingl PJ, Cohen RD, Sholtz RI, Ferrara A, Christianson RE, van den Berg BJ, Siiteri PK. (2003) DDT and DDE exposure in mothers and time to pregnancy in daughters. The Lancet 361(9376):2205-2206.

Cooper GS, Savitz DA, Milikan R, Chiu Kit T. (2002) Organochlorine exposure and age at natural menopause. Epidemiology 13(6):729-733.

Cooper GS, Klebanoff MA, Promislow J, Brock JW, Longnecker MP. (2005) Polychlorinated biphenyls and menstrual cycle characteristics. Epidemiology 16(2):191-200.

Dewalque L, Charlier C. (2012) Masculine fertility threatened by the presence of endocrine disruptors in environment? Revue Medicale de Liege 67(5-6):243-249.

Ehrlich S, Williams PL, Missmer SA, Flaws JA, Berry KF, Calafat AM, Ye X, Petrozza JC, Wright D, Hauser R. (2012) Urinary bisphenol A concentrations and implantation failure among women undergoing in vitro fertilization. Environmental Health Perspective 120(7):978-983.

Eskenazi B, Warner M, Mocarelli P, Samuels S, Needham LL, Patterson Jr, DG, Lippan S, Vercellini P, Gerthoux PM, Brambilla P, Olive D. (2002) Serum dioxin concentrations and menstrual cycle characteristics. American Journal of Epidemiology 156(4):383-392.

Farr SL, Cooper GS, Cai J, Savitz DA, Sandler DP. (2004) Pesticide use and menstrual cycle characteristics among premenopausal women in the agricultural health study. American Journal of Epidemiology 160(12):1194-1204.

Foster WG, Neal MS, Han MS, Dominguez MM. (2008) Environmental contaminants and human infertility: hypothesis or cause for concern? Journal of Toxicology and Environmental Health B Critical Reviews 11(3-4):162-176.

Gerhard I, Monga B, Krahe J, Runnebaum B. (1999) Chlorinated hydrocarbons in infertile women. Environmental Research Section A. 80(4):299-310.

Giwercman A. (2011) Estrogens and phytoestrogens in male infertility. Current Opinion in Urology 21(6):519-526.

Grady R, Sathyanarayana S. (2012) An update on phthalates and male reproductive development and function. Current Urology Reports 13(4):307-310.

Greenlee A, Arbuckle T, Chyou P. (2003) Risk factors for female infertility in an agricultural region. Epidemiology 14(4):429-436.

Gregoraszczuk EL, Ptak A. (2013) Endocrine-Disrupting Chemicals: Some Actions of POPs on Female Reproduction. International Journal of Endocrinology doi:10.1155/2013/828532.

Hunt PA, Koehler KE, Susiarjo M, Hodges CA, Ilagan A, Voigt RC, Thomas S, Thomas BF, Hassold TJ. (2003) Bisphenol A exposure causes meiotic aneuploidy in the female mouse. Current Biology 13(7):546-553.

Petrelli G, Figà-Talamanca I. (2001) Reduction in fertility in male greenhouse workers exposed to pesticides. European Journal of Epidemiology 17(7):675-677.

Toshima H, Suzuki Y, Imai K, Yoshinaga J, Shiraishi H, Mizumoto Y, Hatakeyama S, Onohara C, Tokuoka S. (2012) Endocrine disrupting chemicals in urine of Japanese male partners of subfertile couples: a pilot study on exposure and semen quality. International Journal Hygiene and Environmental Health 215(5):502-506.


5. Spontaneous Abortion

Health Risk
Environmental chemicals in our environment may be causing spontaneous abortions in exposed women and men. Spontaneous abortion is defined as the loss of a fetus weighing less than 500 grams before 20 weeks gestation counted from the first day of the last menstrual period. The known causes of spontaneous abortion in the first trimester are primarily chromosomal abnormalities. In the second trimester, spontaneous abortions are often attributed to uterine abnormalities. Risk factors for spontaneous abortion include advanced maternal age, increasing parity, and increasing paternal age preconception solvent exposure of fathers and maternal heavy lifting. Other factors that are known to cause spontaneous abortion are therapeutic agents such as chemotherapy, radiation and anesthetic agent exposures. Tobacco and ethanol exposure also have an impact, alone and in combination. Substance abuse related to cocaine and other drugs is also associated with fetotoxic responses. Paternal exposures to toxicants may also play a role in the etiology of spontaneous abortion through two proposed mechanisms: (1) direct effects on the germ cells; or (2) indirect effects by the transmission of the toxicant to the mother and fetus through the seminal fluid or maternal and fetal exposures brought home by the father.

The incidence of spontaneous abortion is estimated to be 50% of all pregnancies, based on the assumption that many pregnancies abort spontaneously with no clinical recognition. The frequency of spontaneous abortions in Ontario between 1979 and 1984 were calculated from data on hospital admissions for all Ontario hospitals. In this study the frequency of clinically recorded spontaneous abortions were found to be steady over the time period 1979 to 1984 ranging between 6.8 and 7.2%. Several Ontario counties consistently experienced high rates of spontaneous abortions although the reasons remain undetermined. These data suggest that overall there appears to be no increase in spontaneous abortion, at least for Ontario, but there is evidence that there may be regional effects where investigation of the cause is warranted. However as these data are based on hospital admissions and the majority of women who experience a spontaneous abortion are not admitted to hospital, these data are an underestimate of the true rate of clinically recognized pregnancy loss. The self-reported rates of spontaneous abortion range from 10 to 20 percent and the early abortions in particular are likely influenced by how aware the woman is of her menstrual cycle.

There is evidence that organochlorine and carbamate pesticides cross the placenta and possibly cause fetal death. Another Indian study reported that wives of worker's exposed to organochlorine pesticides had elevated risk of spontaneous abortion and stillbirth. In a study of couples living and working on Ontario farms, increased miscarriage rates were observed when certain pesticides (atrazine, glyphosate, 2,4-D, 2,4-DB, MCPA, carbaryl, thiocarbamates, and insecticides), were applied in the 3-month window of time before conception. Pesticides associated with increased risk of miscarriage when exposure occurred during the first trimester of pregnancy were atrazine, dicamba, and 2,4-D. Several studies have also reported increased risk of miscarriage in occupations associated with agriculture (e.g., gardeners, greenhouse workers, veterinarians). Women exposed to hexachlorobenzene (HCB) as children, who developed severe porphyria cutanea tarda, have been followed for approximately 40 years. The residues are still present in many of the survivors. During a review of the reproductive outcomes of these women, an unexpected finding was the association of high serum concentrations of HCB with high rates of spontaneous abortion. No effect of polybrominated biphenyl contamination of the food supply in Michigan in the mid-1970s on spontaneous abortion could be found in another study. Low to moderate blood lead levels have been associated with increased risks of spontaneous abortion. Other heavy metals such as mercury may also be fetotoxic. There is suggestive evidence that women exposed to substances produced by molds, some of which are highly estrogenic, in grain have a 2-fold increase in risk of spontaneous abortion in addition to estrogen-related cancer. Paternal exposure to oil and oil products was not associated with an increase in the risk for spontaneous abortion in one study. Both maternal and paternal occupational exposure to organic solvents have been linked with increased rates of miscarriage. Taken together these data suggest that spontaneous abortion is affected by occupation, contaminant, and level of exposure. There is also evidence that the risk factors for early spontaneous abortions (< 12 weeks) differ from later abortions (12 - 19 weeks).

A number of reports have shown that chemical contaminants are detectable in human serum and ovarian follicular fluid of both pregnant and non-pregnant women, respectively. Contaminants such as herbicides, lead, mercury, dioxins, drugs, and tobacco smoke by-products have also been measured in seminal fluid. These data suggest that potential toxic agents are present in the body and in some cases may achieve concentrations in target tissues sufficient to induce an adverse effect. In one study, HCB treatment induced decreased levels of serum progesterone in the luteal phase of the menstrual cycle in cynolmogus monkeys. The mechanism is not understood, although it may involve a reduction in steroid metabolizing function in the ovary. The persistence of this chemical in fat could explain an effect observed over many years. Several in vitro studies have demonstrated that environmental contaminants such as HCB, PCBs, dioxins, and DDE alter steroid hormone enzymes that are both involved in the production of gonadal steroids and their metabolism.

While in none of the above cases has a causal link between pesticide exposure and an environmental contaminant or the relevant mechanism involved been established, a number of pesticides have been shown to have estrogenic or anti-progestagenic activity. Elevated estrogen may be toxic to the conceptus prior to implantation and thus induce early fetal loss. It is well known that high doses of estrogen, the so-called "morning after pill" can be used to prevent implantation following unprotected intercourse. Progesterone is critical for implantation and the maintenance of human pregnancy. Therefore, compounds that impair progesterone production increase its metabolism or block its action that is of most interest. Interference with either progesterone production by removing the corpus luteum, or alternatively inhibiting progesterone function by administration of an antiprogestin such as mifepristone (RU-486), can result in a spontaneous abortion. These observations suggest theoretical mechanisms by which environmental chemicals might induce abortions but dose considerations cast some doubt on the probability that low-level environmental chemical exposures would have an effect, unless the chemicals were persistent in the body.

It is clear that there is an increased risk of spontaneous abortion with high level exposure as shown for some occupational groups. However, there are substantial gaps in our knowledge about whether exposure to environmental chemicals has an impact on spontaneous abortion for the general population.


Useful Links
American Academy of Family Physicians: Management of Spontaneous Abortion

Clinical Key (Elsevier): Spontaneous Abortion-Causes, Diagnosis & Treatments

Mayo Clinic: Miscarriage

Medicine World: Spontaneous Abortion

The Merck Manual: Spontaneous Abortion


Further Reading
Arbuckle TE, Lin Z, Mery LS. (2001) An exploratory analysis of the effect of pesticide exposure on the risk of spontaneous abortion in an Ontario farm population. Environmental Health Perspectives 109(8):851-857.

Brieño-Enríquez MA, Reig-Viader R, Cabero L, Toran N, Martínez F, Roig I, Garcia Caldés M. (2012) Gene expression is altered after bisphenol A exposure in human fetal oocytes in vitro. Molecular Human Reproduction 18(4):171-183.

Crisostomo L, Molina VV. (2002) Pregnancy outcomes among farming households of Nueva Ecija with conventional pesticide use versus integrated pest management. International Journal of Occupational and Environmental Health 8(3):232-242.

Eskenazi B, Mocorelli P, Warner M, Chee W, Gerthoux PM, Samuels S, Needham LL, Patterson DG. (2003) Effect of maternal dioxin exposure on birth outcomes. Maternal serum dioxin levels and birth outcomes in women of Seveso, Italy. Environmental Health Perspectives 111(7):947-953.

Gu PQ, Gao LJ, Li L, Liu Z, Luan FQ, Peng YZ, Guo XR. (2012) Endocrine disruptors, polychlorinated biphenyls-induced gC1qR-dependent apoptosis in human trophoblast cell line HTR-8/SVneo. Reproductive Sciences 19(2):181-189.

Korrick SA, Chen C, Damokosh AI, Ni J, Liu X, Cho S, Altshul L, Rayan L, Xu X. (2001) Association of DDT with spontaneous abortion: a case-control study. Annals of Epidemiology 11(7):491-496.

Petrelli G, Figà-Talamanca I, Lauria L, Mantovani A. (2003) Spontaneous abortion in spouses of greenhouse workers exposed to pesticides. Environmental Health and Preventive Medicine 8(3):77-81.

Salazar-Garcia F, Gallardo-Diaz E, Ceron-Mireles P, Loomis D, Borja-Aburto VH. (2004) Reproductive effects of occupational DDT exposure among male malaria control workers. Environmental Health Perspectives 112(5):542-547.

Schnorr TM, Lawson CC, Whelan EA, Dankovic DA, Deddens JA, Piacitelli LA, Reefhuis J, Sweeney MH, Connally LB, Fingerhut MA. (2001) Spontaneous abortion, sex ratio, and paternal occupational exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin. Environmental Health Perspectives 109(11):1127-1132.

Schreinemachers DM. (2003) Birth malformations and other adverse perinatal outcomes in four U.S. wheat-producing states. Environmental Health Perspectives 111(9):1259–1264.

Shaw GM, Nelson V, Iovannisci D, Finnell R, Lammer EJ. (2003) Genetic susceptibility, chemical exposures and birth defects. Maternal occupational exposures and biotransformation genotypes as risk factors for selected congenital anomalies. American Journal of Epidemiology 157(6):475-484.

Sugiura-Ogasawara M, Ozaki Y, Sonta S, Makino T, Suzumori K. (2005) Exposure to bisphenol A is associated with recurrent miscarriage. Human Reproduction 20(8):2325-2329.

Torres-Arreola L, Berkowitz G, Torres-Sánchez L, López-Cervantes M, Cebrián ME, Uribe M, López-Carrillo L. (2003) Preterm birth in relation to maternal organochlorine serum levels.  Annals of Epidemiology 13(3):158-162.

Weselak M, Arbuckle TE, Walker MC, Krewski D. (2008) The influence of the environment and other exogenous agents on spontaneous abortion risk. Journal of Toxicology and Environmental Health B Critical Reviews 11(3-4):221-241.


6. Sex Ratios

Health Risk
The number of human males, relative to females, born in North America and elsewhere in the world, has been declining for several decades. The cause of this change is unknown however environmental chemical exposure is suspected to play a role. The sex ratio is calculated by dividing the number of live male births by the total number of births for a given period of time. Although there is poor understanding of factors that alter the sex ratio, there is clear evidence that external influences are associated with such a change. These factors can be grouped into medical, occupational and environmental causes.

The reported medical factors shown or suggested to reduce the male proportion of offspring include older age fathers and mothers, in vitro fertilization, ovulation induction, non-Hodgkin's lymphoma, hepatitis and multiple sclerosis. Also, men who develop testicular cancer tend to father more female children than are characteristic of men in the general population.

A study of offspring born from 1978 to 1990 in the Netherlands revealed an increase in daughters when men had workplace exposure to pesticides. Other occupational exposures reported to be associated with a change in the sex ratio have included working in the aluminum industry as "carbon setters", "anode setters" or "carbon changers" and exposure to waste anesthetic gases.

Changes in the sex ratio have been reported following the accidental release of dioxin into the environment in Seveso, Italy. Although these data suggest an association between exposure to an environmental contaminant and altered birth sex ratio this report must be interpreted with caution due to the relatively small sample size involved. Moreover, this finding has not been supported by observations of altered sex ratios of children from other dioxin exposed populations.

Sex ratios in Canada, United States, Denmark and the Netherlands have been shown to decrease over a period of between 20 to 30 years. Similar changes have been reported for other countries although these data must be regarded with caution due to sample size limitations.

Although a decreasing trend in sex ratio has been reported in the Netherlands in one study, a trend towards an increase in the sex ratio has been reported for Italy, Greece and the Netherlands. Regression analysis of temporal trends in sex ratio of live births between 1969 and 1995 in the United States revealed a significant decline among whites for the 27 years under study (OR=0.9935; 95% CI 0.9919 - 0.9952). In contrast the sex ratio among blacks during the same time period revealed a significant increase in the sex ratio (OR 1.0208, 95% CI 1.0162 - 1.0254). There is also a suggestion in the literature that changes in sex ratio may precede environmental contamination with industrial chemicals.

In animal studies the sex ratio of animals treated with various test compounds has been shown to be altered. However, apart from documenting a change in the sex ratio of the offspring no insight has been provided as to a possible mechanism for the observed change.

Very little information is present in the literature that addresses the factors affecting the sex ratio. Two separate hypotheses provide limited insight into the mechanism(s) affecting sex ratio in animals. It has been suggested that the developmental rate of the conceptus differs on the basis of genetic sex. It is assumed that shorter intervals between cell divisions increases a cells vulnerability to toxic insult and thus the more rapid growth of the male fetus increases susceptibility to lethal changes that will ultimately affect the sex ratio. Secondly, in mice, the position of a female fetus during pregnancy (between two males vs. between two females) has been shown to affect the sex ratio of her offspring. These data suggest that hormonal environment during gestation is a factor that subsequently affects sex ratio of the offspring when they begin having litters. However, the mechanism(s) underlying these changes have not been explored and both hypotheses have yet to be experimentally evaluated.

While there is evidence for a decrease in the number of males being born in some regions, the literature is equivocal with some reports demonstrating no change and others finding divergent effects depending on race. Furthermore, lacking a credible biological mechanism to explain the observed effects the overall conclusion is that the evidence linking exposure to environmental contaminants and changing sex ratio at this time is very weak.


Useful Links
Centers for Disease Control and Prevention (CDC): Sex Ratio and the Environment

Encyclopedia of Earth: Endocrine disrupting chemicals and gender

Minnesota Department of Health (US)-Sex Ratio: Facts & Figures

United Nations Environment Programme (UNEP): State of the science of endocrine disrupting chemicals – 2012. Chapter 2.4 Endocrine disrupting chemicals and sex ratio in humans and wildlife


Further Reading
Davis DL, Gottlieb MB, Stampnitzky JR. (1998) Reduced ratio of male to female births in several industrial countries: a sentinel health indicator? JAMA 279(13):1018-1023.

Ishihara K, Warita K, Tanida T, Sugawara T, Kitagawa H, Hoshi N. (2007) Does paternal exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affect the sex ratio of offspring? Journal of Veterinary Medical Science 69(4):347-352.

Ishihara K, Ohsako S, Tasaka K, Harayama H, Miyake M, Warita K, Tanida T, Mitsuhashi T, Nanmori T, Tabuchi Y, Yokoyama T, Kitagawa H, Hoshi N. (2010) When does the sex ratio of offspring of the paternal 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposure decrease: in the spermatozoa stage or at fertilization? Reproductive Toxicology 29(1):68-73.

James WH. (2006) Offspring sex ratios at birth as markers of paternal endocrine disruption. Environmental Research 100(1):77-85.

Karmaus W, Huang S, Cameron L. (2002) Parental concentration of dichlorodiphenyl dichloroethane and polychlorinated biphenyls in Michigan fish eaters and sex ratio. Journal of Occupational and Environmental Medicine 44(1):8-13.

Larsson DGJ, Hällman H, Förlin L. (2005) Skewed embryonic sex ratios in a viviparous fish: a result of endocrine disruption? Marine Environmental Research 50(1–5):191–192.

Mackenzie CA, Lockridge A, Keith M. (2005) Declining Sex Ratio in a First Nation Community. Environmental Health Perspectives 113(10):1295-1298.

Mocarelli P, Gerthoux PM, Ferrari E, Patterson DG, Kieszak SM, Brambilla P, Vincoli N, Signorini S, Tramacere P, Carreri V, Sampson EJ, Turner WE. (2000) Paternal dioxin exposure and offspring sex ratio Paternal concentrations of dioxin and sex ratio of offspring. Lancet 355(9218):1858-1863.

Møller H. (1998) Trends in sex-ratio, testicular cancer and male reproductive hazards: are they connected? APMIS 106(1):232-238.

Ryan JJ, Amirova Z, Carrier G. (2002) Sex ratios of children of Russian pesticide producers exposed to dioxin. Environmental Health Perspectives 110(11):A699-701.

Terrell ML, Hartnett KP, Marcus M. (2011) Can environmental or occupational hazards alter the sex ratio at birth? A systematic review. Emerging Health Threats Journal 4:7109 doi:103402/ehtjv4i07109.

van Larebeke NA, Sasco AJ, Brophy JT, Keith MM, Gilbertson M, Watterson A. (2008) Sex ratio changes as sentinel health events of endocrine disruption. International Journal of Occupational and Environmental Health 14(2):138-143.


7. Testicular Cancer

Health Risk
The incidence of testicular cancer in western countries has increased steadily in the past 40-50 years. The etiology of testicular cancer is not well understood, but there is sufficient evidence to postulate a link with endocrine modulating substances. Testicular cancer is a rare cancer, with an age-adjusted incidence of 4.2/100,000 in Canada. This accounts for 1.1% of all malignant neoplasms in Canadian males. Despite the low overall incidence of testicular cancer, it is the most common malignancy among young men, 25-34 years old. Testicular cancer varies notably with race, with incidence rates about threefold higher in Caucasians compared to African Americans in the US.

The incidence rate of testicular cancer has been increasing since the middle of the 20th century in many western countries, including Canada, the United States, the Nordic Countries, and Britain. The trend has been especially rapid in eastern European countries such as Slovenia. Countries with a sufficiently long period of cancer registration, such as Denmark, document this trend back to the first half of the 20th century. Despite the increase in testicular cancer in many western countries, the age-adjusted incidence of testicular cancer is low in all populations of the world. The lowest rates have been observed in Asian populations, African Americans, and black populations in general. The incidence rate in Denmark is in the order of 8 per 100,000, while in Japan and China and in African Americans, the incidence rate is on the order of 1 per 100,000. While the increase in testicular cancer incidence is an important cause of morbidity in young males, testicular cancer is one of the most curable of all solid neoplasms. The five year survival rate has increased during the last 30 years from 63% to over 90%. The present case fatality rate is 10-15 percent, and even in metastatic cases, cure rates are as high as 80 percent.

The etiology of testicular cancer is poorly understood. Most of the established risk factors are related to in utero events including: cryptochidism or maldescendent testicles, carcinoma in situ and exposure to estrogen in utero. These established risk factors suggest that hormonal exposures may affect testicular cancer risk, particularly exposure to estrogen in utero. However, the exact nature of the link between estrogen exposure and testicular cancer is unclear. It has been suggested that exposure to high levels of estrogen in utero results in the development of carcinoma in situ, which appears to be a precursor of testicular cancer. The associations between estrogen exposure and testicular cancer include an increased risk associated with: nausea in pregnancy resulting from high endogenous estrogen levels, DES exposure, and non-specified hormone use in pregnancy. In addition to these exposures, endogenous maternal estrogen levels are higher in first pregnancies as compared to subsequent ones and several studies have found that children of mothers with high parity have a decreased risk of testicular cancer when compared to male children of nulliparous mothers. Twin studies have observed that dizygotic twin pregnancies have higher maternal hormones levels than monozygotic pregnancies. As a result, dizygotic twins have a higher risk of testicular cancer than monozygotic twins. Finally, maternal smoking may be protective of testicular cancer, possibly be due to increased turnover of estrogen in cigarette smokers. It would appear that estrogen has an important role in the etiology of testicular cancer, and warrants further study.

Testicular germ cell tumors in adults are a well described cytogenetic entity. They have a chromosome number in the triploid range, and are characterized by specific chromosomal gains at chromosomes 7, 8, 12, 21, and X, and by specific chromosomal losses at chromosomes 11, 13, and 18. A non-random genetic alteration has been localized to i(12p). Studies have shown that 80% of testicular tumors have one or more copies of i(12). It would seem that isochromosome 12p is the recurrent structural chromosomal abnormality of these tumors. It has been estimated that 33.4% of all cases of testicular cancer are in individuals with the malignant genotype, assuming it is a recessive trait.

Other risk factors of testicular cancer that have been examined include: occupation, chemical exposure, radiation exposure, socio-economic status, and diet. Recent studies regarding testicular cancer risk and diet have pointed to a risk associated with dairy products. In addition to fats, protein and calcium, milk and dairy products contain considerable amounts of female sex hormones such as estrogens and progesterone. These hormones are a result of the fact that present-day milk is produced from pregnant cows. A significant elevated risk of testicular cancer has been linked to exposure to polyvinyl chloride; however this has yet to be confirmed.

The types of testicular cancer commonly found in humans are preceded by atypical intratubular germ cells termed CIS (carcinoma in situ) which is extremely rare in laboratory animals. Until recently, experimental animal models appropriate for extrapolation to humans were lacking. CIS like lesions have been induced in rabbits exposed in utero and/or in infancy to the toxicants octylphenol, p,p'- DDT/DDE or zeranol. These results illustrate the potential relevance of the rabbit as a model for this type of cancer in humans. However, validated animal models for germ cell (testicular) tumors observed in man currently do not exist.

Despite the absence of direct human evidence, the role of man-made chemicals can contribute to the pathogenesis of testicular cancer development by the estrogenetic/anti-androgenetic effect of the hormones on the testes. However, the hormonally active environmental chemicals involved, the pathways in which they act, and their associated risk of cancer remain unknown.

The etiology of testicular cancer remains unknown. However, many of the risk factors point towards a hormonal mechanism of carcinogenesis. Currently there is a lack of direct evidence regarding the link between environmental endocrine disrupting chemicals and testicular cancer risk. As well, the link between estrogenic or anti-androgenic compounds and testicular cancer has not yet been examined. In addition, the current lack of a suitable animal model prevents definitive conclusions on the role of hormonally active environmental chemicals on testicular cancer risk.


Useful Links
American Cancer Society: Testicular cancer

Canadian Cancer Society: Testicular cancer

Mayo Clinic: Testicular cancer

National Cancer Institute (NCI): Testicular cancer
National Health Service (UK): Testicular cancer - Causes

Testicular Cancer Canada

Testicular Cancer Society (US)


Further Reading
Del-Mazo J, Brieño-Enríquez MA, García-López J, López-Fernández LA, De-Felici M. (2013) Endocrine disruptors, gene deregulation and male germ cell tumors. International Journal of Developmental Biology 57(2-4):225-239.

Ganmaa D, Li XM, Wang J, Qin LQ, Wang PY, Sato A. (2002) Incidence and mortality of testicular and prostatic cancers in relation to world dietary practices. International Journal of Cancer 98(2):262-267.

Garner M, Turner MC, Ghadirian P, Krewski D, Wade M. (2008) Testicular cancer and hormonally active agents.  Journal of Toxicology and Environmental Health B Critical Reviews 11(3-4):260-275.

Giannandrea F, Paoli D, Figà-Talamanca I, Lombardo F, Lenzi A, Gandini L. (2013) Effect of endogenous and exogenous hormones on testicular cancer: the epidemiological evidence. International Journal of Developmental Biology 57(2-4):255-263.

Hardell L, van Bavel B, Lindström G, Carlberg M, Dreifaldt AC, Wijkström H, Starkhammer H, Eriksson M, Hallquist A, Kolmert T. (2003) Increased concentrations of polychlorinated biphenyls, hexachlorobenzene and chlordanes in mothers to men with testicular cancer. Environmental Health Perspectives 111(7):930-934.

Hardell L, Van Bavel B, Lindstrom G, Carlberg M, Eriksson M, Dreifaldt AC, Wijkstrom H, Starkhammar H, Hallquist A, Kolmert T. (2004) Concentrations of polychlorinated biphenyls in blood and the risk for testicular cancer. International Journal of Andrology 27(5):282–290.

Nori F, Carbone P, Giordano F, Osborn J, Figà-Talamanca I. (2006) Endocrine-disrupting chemicals and testicular cancer: a case-control study. Archives of Environmental and Occupational Health 61(2):87-95.

Ohlson CG, Hardell L. (2000) Testicular cancer and occupational exposures with a focus on xenoestrogens in polyvinyl chloride plastics. Chemosphere 40(9-11):1277-1282.

Vega A, Baptissart M, Caira F, Brugnon F, Lobaccaro JM, Volle DH. (2012) Epigenetic: a molecular link between testicular cancer and environmental exposures. Frontiers in Endocrinology 3:150 doi:10.3389/fendo.2012.00150.


8. Ovarian Cancer

Health Risk
The etiology of ovarian cancer is poorly understood; however, evidence of a possible relationship between environmental exposures and the risk of ovarian cancer does exist. Ovarian cancer is both the fifth most diagnosed cancer (accounting for 4% of all new cancers) and the fifth leading cause of cancer deaths (accounting for almost 5%) among Canadian women. Our knowledge of the risk factors for ovarian cancer is mainly related to hormonal and reproductive factors, including nulliparity, late age at menopause, family history of ovarian and breast cancer, and infrequent oral contraceptive use. Epidemiologic studies, animal experiments, and receptor binding studies suggest that malignant ovarian tumors may be endocrine related and hormone dependent. The hormone-dependency of ovarian cancer has led to the hypothesis that exogenous estrogenic compounds may play a role in the etiology of this cancer. Pesticides with endocrine disrupting activity remain legally or illegally in use in different countries, including organochlorine, organophosphorous, arsenic and mercury compounds, phenoxy acid herbicides, atrazine and dithiocarbamates. Scientific research to date suggests a link between atrazine and ovarian cancer.

Incidence and mortality rates for ovarian cancer have been relatively stable over time, though a modest decline in mortality has been observed. With approximately 2,600 new cases and 1,500 deaths annually, ovarian cancer is the leading cause of death from all gynecologic malignancies in Canada. The disease affects elderly and middle aged women with the highest incidence rates reported in North America and Northern Europe. Over the past 40 years, the rate of ovarian cancer mortality has increased among women aged 65 years and older. The incidence of ovarian cancer increases with age; it is relatively rare in women younger than 30 year of age, with only 1.5/100,000 women diagnosed annually in the 20-30 year age group, and 49/100,000 women diagnosed annually in the 60-69 year age group.

The etiology of ovarian cancer is largely unknown. Most established risk factors for the disease relate to reproductive events. Several case-control studies have found a decrease in risk of the epithelial ovarian cancer associated with pregnancy, breast feeding, and use of oral contraceptives (OCs). This prompted the hypothesis of incessant ovulation, which holds that factors which suppress ovulation may reduce the risk of developing ovarian cancer (Franceschi 1989). In a multicenter population-based, case-control study, the estimated relative risk of epithelial ovarian cancer was 0.5 (95% confidence interval 0.5 to 0.7) for women who had ever used oral contraceptives. The estimated risk reduction that occurred with oral contraceptives was 34% with any use, and this reduction increased to 70% with use for 6 or more years. However, several investigators have hypothesized that exposure to environmental toxicants such as pesticides and herbicides can be linked to ovarian cancer. Ovarian cancer has been linked with triazine herbicide exposure in a number of studies. In a case-control study by Donna (1989), women with previous exposure to triazine herbicides showed a two to threefold risk of epithelial ovarian cancer as compared to unexposed women. An association between atrazine and ovarian tumors has been observed in two Italian studies (Donna et al., 1984, 1989). However, two epidemiologic studies have suggested that atrazine may be carcinogenic to humans. Aside from phenoxy acid herbicides, atrazine is the most commonly used herbicide worldwide (Short & Colborn, 1999) and is used in the cultivation of corn, fruits, vegetables and grapes for producing wine. Atrazine has been classified as a possible human carcinogen by the International Agency on Cancer (IARC 1999).

A study by Wetzel et al. demonstrated that feeding Sprague-Dawley rats with a high dose of atrazine lengthened their estrus cycle, increased the number of days in estrus, and given in conjunction with estrogen, induced an earlier onset of mammary tumors (Wetzel et al., 1994). Atrazine is a genotoxic compound which induces DNA damage in some cells and increases mammary tumors in rats (but not in mice) treated orally.

The causes of ovarian cancer are poorly understood; however, a number of risk factors have been associated with either an increased or decreased likelihood of developing the disease. Epidemiologic studies, animal experiments, and receptor binding studies indicate that both normal ovaries and many malignant ovarian tumors are endocrine related and hormone dependent. The association between ovarian cancer and endogenous or hormonally related events has led to the hypothesis that exposure to exogenous compounds in the environment may increase the risk of this cancer.

Taken together, the evidence of an association between ovarian cancer and environmental toxins is limited, but remains an important issue to consider in future studies of this cancer.


Useful Links
American Cancer Society: Ovarian cancer

Canadian cancer Society: Ovarian cancer

Mayo Clinic: Ovarian cancer

National Cancer Institute (NCI): Ovarian cancer

National Health Service (UK): Ovarian cancer

Ovarian Cancer Canada

Ovarian Cancer National Alliance


Further Reading
Donna A, Betta PG, Robutti F, Crosignani P, Berrino F, Bellingeri D. (1984) Ovarian mesothelial tumors and herbicides: a case-control study. Carcinogenesis 5(7):941-942.

Donna A, Crosignani P, Robutti F, Betta PG, Bocca R, Mariani N, Ferrario F, Fissi R, Berrino F. (1989) Triazine herbicides and ovarian epithelial neoplasms. Scandinavian Journal of Work, Environment and Health 15(1):47-53.

Franceschi S. (1989) Reproductive factors and cancers of the breast, ovary and endometrium. European Journal of Cancer and Clinical Oncology 25(12):1933-43.

Hall JM, Korach KS. (2012) Endocrine disrupting chemicals promote the growth of ovarian cancer cells via the ER-CXCL12-CXCR4 signaling axis. Molecular Carcinogenesis doi:10.1002/mc.21913

Hwang KA, Kang NH, Yi BR, Lee HR, Park MA, Choi KC. (2013) Genistein, a soy phytoestrogen, prevents the growth of BG-1 ovarian cancer cells induced by 17β-estradiol or bisphenol A via the inhibition of cell cycle progression. International Journal of Oncology 42(2):733-740.

Hwang KA, Park SH, Yi BR, Choi KC. (2011) Gene alterations of ovarian cancer cells expressing estrogen receptors by estrogen and bisphenol a using microarray analysis. Laboratory Animal Research 27(2):99-107.

IARC Monographs on the Evaluation of Carcinogenic Risks to Human. (1999) World Health Organization International Agency for Research on Cancer, Vol. 73. Lyon, France. pp. 59-113.    

Kang NH, Hwang KA, Kim TH, Hyun SH, Jeung EB, Choi KC. (2012) Induced growth of BG-1 ovarian cancer cells by 17β-estradiol or various endocrine disrupting chemicals was reversed by resveratrol via downregulation of cell cycle progression. Molecular Medicine Reports 6(1):151-156.

Koifman S, Koifman RJ, Meyer A. (2002) Human reproductive system disturbances and pesticide exposure in Brazil. Cadernos de Saude Publica 18(2):435-445.

Park SH, Kim KY, An BS, Choi JH, Jeung EB, Leung PC, Choi KC. (2009) Cell growth of ovarian cancer cells is stimulated by xenoestrogens through an estrogen-dependent pathway, but their stimulation of cell growth appears not to be involved in the activation of the mitogen-activated protein kinases ERK-1 and p38. Journal of Reproductive Development 55(1):23-29.

Salehi F, Dunfield L, Phillips KP, Krewski D, Vanderhyden BC. (2008) Risk factors for ovarian cancer: an overview with emphasis on hormonal factors. Journal of Toxicology and Environmental Health B Critical Reviews 11(3-4):301-321.

Shields T, Gridley G, Moradi T, Adami J, Plato N, Dosemeci M. (2002) Occupational exposures and the risk of ovarian cancer in Sweden.  American Journal of Industrial Medicine 42(3):200-213.

Short P, Colborn T. (1999) Pesticide use in the U.S. and policy implications: a focus on herbicides. Toxicology and Industrial Health 15(1-2):240-275.

Wetzel LT, Luempert LG 3rd, Breckenridge CB, Tisdel MO, Stevens JT, Thakur AK, Extrom PJ, Eldridge JC. (1994) Chronic effects of atrazine on estrus and mammary tumor formation in female Sprague-Dawley and Fischer 344 rats. Journal of Toxicology and Environmental Health 43(2):169-82.


9. Prostate Cancer

Health Risk
Human exposure to hormonally active chemicals is contributing to the rise in prostate cancer rates. Prostate cancer is an androgen-dependent disease that is rare before age 50 years, incidence rates increasing steeply at older ages. The lifetime risk of developing prostate cancer is estimated to be 11% and the likelihood of dying from this disease is 3.6%. There will be an estimated 189,000 new cases and 30,200 deaths from prostate cancer in United States during 2002. Prostate cancer incidence and mortality rates among U.S. Blacks are the highest in the world. As assessed by studies of familial clusters, genetic factors alone likely explain less than 10% of prostate cancers.

Prostate cancer incidence rates have increased substantially in several countries since about 1970. Introduction and widespread use of the PSA (prostate-specific antigen) blood test that enables early prostate cancer detection is thought to account for sharply increased prostate cancer incidence rates observed during the late 1980's. Prostate cancer death rates also increased after 1970 but less dramatically than incidence rates. Both incidence and mortality rates appear to have declined slightly during the past few years. Moreover, it is now clear that there are at least two forms of the disease, a slow growing cancer that remains in the prostate gland which is very common and a rapidly-growing, metastasizing form that causes clinically-relevant prostate cancer. The relationship between these two forms of the disease is not clear. The reasons for prostate cancer increases before the late 1980's may have included both a true increased risk and improved diagnosis because of safer surgical procedures and a more aggressive approach toward treatment of older men.

Most prostate cancers are dependent on male hormones (androgens) that bind to androgen receptors in prostate cells and stimulate their growth and function. Anti-androgen drugs have been used to treat benign and malignant prostate disease and are being tested for ability to prevent prostate cancer. There is preliminary evidence that altered male hormone balance may increase prostate cancer risk. This raises the possibility that mutations in the AR gene or exposure to environmental chemicals with hormonally active chemicals could modulate prostate cancer risk; for instance, recent evidence suggests that the elevated risk among U.S. Blacks may be caused in part by racial differences in AR gene polymorphisms. Increased prostate cancer risks have also been linked to polymorphisms in CYP17 and GSTP I, genes that encode enzymes that can activate or inactivate environmental carcinogens.

No strong external risk factors have been identified for prostate cancer. Most known or suspected risk factors could act through hormonal mechanisms but direct evidence is generally lacking; they could also act through non-hormonal mechanisms such as genotoxicity. There is limited, often inconsistent epidemiologic evidence for dietary factors that may reduce (vegetables, fruits, tomato products, cabbage, brussels sprouts, cauliflower, beans, peanuts, soy foods, selenium, vitamin E, beta-carotene, lycopenes) or increase (animal fat, red meats, dairy products, calcium, cured meat) the risk of prostate cancer. Five cohort studies of vegetarians, however, showed no reduction of prostate cancer risks. Diets high in fat and simple carbohydrates tend to raise insulin and insulin-like growth factor levels; the latter promote increased sex steroid synthesis, stimulate cell proliferation and have been linked to increased prostate cancer risks. Occupational exposures linked to increased risk of prostate cancer include: farming, pesticides, metal fabricating, and activities involving exposure to metallic dusts, cutting oils, and paints/varnishes. Evidence linking smoking to incident prostate cancer is mixed but risk was increased 2-3 times among men with high body mass index who started smoking before age 20 years or were heavy smokers. There is mixed evidence of a role for alcohol consumption in prostate cancer.

Prostatic hypertrophy has been demonstrated in various rodent experiments following treatment with estrogenic chemicals. These effects have been shown to occur at low concentrations. However, it should be noted that, although similar experimental protocols have been followed, other investigators have been unable to reproduce these findings. Moreover, even though the dose levels are considered to be low relative to the concentrations necessary to induce other adverse effects with these toxicants, the concentrations still considerably exceed the concentrations present in low dose birth control pills and thus these changes may not necessarily be considered low dose effects. Changes in prostate gland growth in rodents have been suggested to indicate that similar changes may occur in humans. However, the extent to which chemical effects on rodent prostate gland development can be used to predicting risk of human prostate cancer is not clear, given the differences in gland anatomy and the fact that few rodents spontaneously develop prostate cancer. Furthermore, the mechanism of environmental contaminant induced changes in prostate gland differentiation and growth have yet to be elucidated.

In the absence of direct human evidence (demonstrated exposure, association between exposure and increased risk of prostate cancer, and evidence of contaminant induced changes in circulating levels of sex steroids of affected men compared to a reference population), there remains the theoretical possibility that hormonally active chemicals may modulate prostate cancer risk by altering sex steroid balance in men. However, the hypothesis that human exposure to hormonally active environmental chemicals is associated with an increased risk for the development of prostate cancer remains to be tested.

Despite much research, the main proven risk factors for prostate cancer risk are non-modifiable: age, family history, and race. Epidemiologic research on potential modifiable risk factors has shown associations with diet, occupation, lifestyle and other factors. At present, the inconsistencies and inadequacies of existing studies do not permit a conclusion that hormonally active chemicals are potential causative factors in prostate cancer.


Useful Links
American Cancer Society: Prostate cancer

Canadian cancer Society: Prostate cancer

Mayo Clinic: Prostate cancer

National Cancer Institute (NCI): Prostate cancer

National Health Service (UK): Prostate cancer

Prostate Cancer Canada

Prostate Cancer Foundation


Further Reading
Alavanja MC, Samanic C, Dosemeci M, Lubin J, Tarone R, Lynch CF, Knott C, Thomas K, Hoppin JA, Barker J, Coble J, Sandler DP, Blair A. (2003) Use of agricultural pesticides and prostate cancer risk in the agricultural health study cohort American Journal Epidemiology 157(9):800-814.

Hess-Wilson JK, Knudsen KE. (2006) Endocrine disrupting compounds and prostate cancer. Cancer Letter 241(1):1-12.

Hu WY, Shi GB, Hu DP, Nelles JL, Prins GS. (2012) Actions of estrogens and endocrine disrupting chemicals on human prostate stem/progenitor cells and prostate cancer risk. Molecular and Cellular Endocrinology 354(1-2):63-73.

Parent ME, Désy M, Siemiatycki J. (2009) Does exposure to agricultural chemicals increase the risk of prostate cancer among farmers? McGill Journal of Medicine 12(1):70-77.

Prins GS. (2008) Endocrine disruptors and prostate cancer risk. Endocrine Related Cancer 15(3):649-656.

Ragin C, Davis-Reyes B, Tadesse H, Daniels D, Bunker CH, Jackson M, Ferguson TS, Patrick AL, Tulloch-Reid MK, Taioli E. (2013) Farming, reported pesticide use, and prostate cancer. American Journal of Men’s Health 7(2):102-9.

Settimi L, Masina A, Andrion A, Axelson O. (2003) Prostate cancer and exposure to pesticides in agricultural settings. International Journal of Cancer 104(4):458-461.

Sharma-Wagner S, Chokkalingam AP, Malker HS, Stone BJ, McLaughlin JK, Hsing AW. (2000) Occupation and prostate cancer risk in Sweden. Journal of Occupational and Environmental Medicine 42(5):517-525.

Van Maele-Fabry G, Willems JL. (2003) Occupation related pesticide exposure and cancer of the prostate: a meta-analysis. Occupational and Environmental Medicine 60(9):634-642.

Van Maele-Fabry G, Willems JL. (2004) Prostate cancer among pesticide applicators: a meta-analysis. International Archives of Occupational and Environmental Health 77(8):559-570.

Wigle DT, Turner MC, Gomes J, Parent ME. Role of hormonal and other factors in human prostate cancer. Journal of Toxicology and Environmental Health B Critical Reviews 11(3-4):242-259.

Wong O, Raabe GK. (2000) A critical review of cancer epidemiology in the petroleum industry, with a meta-analysis of a combined database of more than 350,000 workers. Regulatory Toxicology and Pharmacology 32(1):78-98.


10. Semen Quality

Health Risk
It has been reported that human sperm counts have been falling around the world and environmental chemicals are suspected as a cause. In 1992 a Danish team of investigators published a report in which they examined all the scientific papers published between 1950 and 1992 containing data on semen quality. A decrease in the concentration of sperm both the number of sperm in a man's ejaculate and the volume of his ejaculate were decreased. This study has received considerable attention and criticism by the scientific community but if nothing else has led to a flurry of studies from around the world, designed to examine for changes in human semen quality. The Danish team reported a global decline in semen quality of approximately 2% per year over the preceding 50 years. Similar trends have been reported in the UK and Paris as well as elsewhere.

A re-analysis of the data from the Danish report has confirmed the original findings. However, in recent years numerous papers have appeared in the scientific press varying results. Some authors have reported a decrease in semen quality over time whereas others have found no change or an increase in semen quality. A number of these studies have shown that there are regional differences in semen quality. For example, the semen quality in men residing in the Thames Water Shed was lower compared to men living outside of the Thames Water Shed. Regional differences in semen quality have also been described in Canada and the United States. Interestingly, in some regions semen quality has been found to be widely divergent from other geographic areas although environmental contamination is similar. A further complication in linking environmental contaminants with effects on semen quality is the disconnection between lower sperm counts and decreased fertility. For example, the time taken to achieve a pregnancy does not appear to be increased in regions for which lower semen quality has been reported.

Exposure to various chemicals has been shown to result in lower semen quality in men in certain occupational settings where exposures are high. Indeed, exposure to the pesticide Kepone and the nemotocide dibromochloropropane (DBCP) resulted in lower sperm counts and in some men complete absence of sperm. In the DBCP example the mechanism of altered sperm counts was found to be due to contaminant induced destruction of the precursor germ cells. While these data demonstrate that semen quality can be reduced by contaminant exposure, and an endocrine target has been adversely affected, an endocrine mechanism has not been shown. Reports of decreased semen quality have not measured exposure and thus it is difficult to infer from these studies that the outcome measured is in any way related to chemical contaminants. Furthermore, while environmental chemicals may induce changes in semen quality the mechanism has yet to be demonstrated. Numerous other factors in addition to potential effects of environmental contaminant are known to affect semen quality. For example, an association between lower semen quality and prescription medications, cigarette smoking, age, heat, and solvent exposure has been documented.

Animal studies using rodents have shown that various industrial chemicals possess the capacity to alter semen quality. Experimental animal studies have shown that chemicals such as methoxychlor, PCBs among others reduce epididymal sperm counts and daily sperm concentration in dosed animals. However, again an endocrine mechanism has not been demonstrated. Two reports have been published and provide an overview of the biological plausibility of an endocrine mechanism that requires testing.

The weight of the evidence supports a conclusion that man-made chemicals can induce changes in human semen quality. However, it has not been shown that such is occurring in the general population or that an endocrine mechanism is involved.


Useful Links
Institut Marques London (UK): Endocrine disruptors and fertility

Mayo Clinic: Healthy Sperm

Regional Fertility Program: Semen Analysis

Stanford University: What Causes Male Infertility?


Further Reading
Dallinga, J.W., Moonen, E.J., Dumoulin, J.C., Evers, J.L., Geraedts, J.P., Kleinjans, J.C. (2002) Decreased human semen quality and organochlorine compounds in blood. Human Reproduction 17(8):1973-1979.

Dalvie M, Myers J, Thompson M, Robins T, Dyer S, Riebow J, Molekwa J, Jeebhay M, Millar R, Kruger P. (2004) The long-term effects of DDT exposure on semen, fertility and sexual function of malaria vector-control workers in Limpopo Province, South Africa. Environmental Research 96(1):1-8.

Hauser R, Altshul L, Chen Z, Ryan L, Overstreet J, Schiff I, Christiani DC. (2002) Environmental organochlorines and semen quality: results of a pilot study. Environmental Health Perspectives 110(3):229-233.

Hauser R, Chen Z, Pothier L, Ryan L, Altshul L. (2003) The relationship between human semen parameters and environmental exposure to polychlorinated biphenyls and p,p'-DDE. Environmental Health Perspectives 111(12):1505–1511.

Jurewicz J, Hanke W, Radwan M, Bonde JP. (2009) Environmental factors and semen quality. International Journal of Occupational Medicine and Environmental Health 22(4):305-329.

Kamijima M, Hibi H, Gotoh M, Taki KI, Saito I, Wang H, Itohara S, Yamada T, Ichihara G, Shibata E, Nakajima T, Takeuchi Y. (2004) A survey of semen indices in insecticide sprayers. Journal of Occupational Health 46(2):109-118.

Li DK, Zhou Z, Miao M, He Y, Wang J, Ferber J, Herrinton LJ, Gao E, Yuan W. (2010) Urine bisphenol-A (BPA) level in relation to semen quality. Fertility and Sterility 95(2):625-630.

Meeker JD, Ehrlich S, Toth TL, Wright DL, Calafat AM, Trisini AT, Ye X, Hauser R. (2010) Semen quality and sperm DNA damage in relation to urinary bisphenol A among men from an infertility clinic. Reproductive Toxicology 30(4):532-539.

Mocarelli P, Gerthoux PM, Patterson DG Jr, Milani S, Limonta G, Bertona M, Signorini S, Tramacere P, Colombo L, Crespi C, Brambilla P, Sarto C, Carreri V, Sampson EJ, Turner WE, Needham LL. (2008) Dioxin exposure, from infancy through puberty, produces endocrine disruption and affects human semen quality. Environmental Health Perspectives 116(1):70-77.

Mocarelli P, Gerthoux PM, Needham LL, Patterson DG Jr, Limonta G, Falbo R, Signorini S, Bertona M, Crespi C, Sarto C, Scott PK, Turner WE, Brambilla P. (2011) Perinatal exposure to low doses of dioxin can permanently impair human semen quality. Environmental Health Perspectives 119(5):713-718.

Phillips KP, Tanphaichitr N. (2008) Human exposure to endocrine disrupters and semen quality. Journal of Toxicology and Environmental Health B Critical Reviews 11(3-4):188-220.

Sharpe RM. (2000) Environment, lifestyle and male infertility. Bailliere's Clinical Endocrinology and Metabolism 14(3):489-503.

Swan SH, Brazil C, Drobnis EZ, Liu F, Kruse RL, Hatch M, Redmon JB, Wang C, Overstreet JW, Study For Future Families Research Group. (2003) Geographic differences in semen quality of fertile U.S. males. Environmental Health Perspectives 111(4):414-420.

Swan SH, Kruse RL, Liu F, Barr DB, Drobnis E, Redmon JB, Wang C, Brazil C, Overstreet JW, Study For Future Families Research Group. (2003) Semen quality in relation to biomarkers of pesticide exposure. Environmental Health Perspectives 111(12):1478–1484.

Toft G, Long M, Krüger T, Hjelmborg PS, Bonde JP, Rignell-Hydbom A, Tyrkiel E, Hagmar L, Giwercman A, Spanó M, Bizzaro D, Pedersen HS, Lesovoy V, Ludwicki JK, Bonefeld-Jørgensen EC. (2007) Semen quality in relation to xenohormone and dioxin-like serum activity among Inuits and three European populations. Environmental Health Perspectives 115(Suppl 1):15-20.

Vested A, Ramlau-Hansen CH, Olsen SF, Bonde JP, Kristensen SL, Halldorsson TI, Becher G, Haug LS, Ernst EH, Toft G. (2013) Associations of in utero exposure to perfluorinated alkyl acids with human semen quality and reproductive hormones in adult men. Environmental Health Perspectives 121(4):453-458.

Yeung BH, Wan HT, Law AY, Wong CK. (2011) Endocrine disrupting chemicals: Multiple effects on testicular signaling and spermatogenesis. Spermatogenesis 1(3):231-239.


11. Male Reproductive Tract Abnormalities

Health Risk
In utero exposure to hormonally active chemicals is contributing to the observed increase in the incidence of male reproductive tract abnormalities. Increases in the incidence of cryptorchidism (failure of the testis to descend into the scrotum) and hypospadias (urethral opening along the shaft of the penis) have been reported. Normal development of the male reproductive tract is dependent on the expression and action of Müllerian inhibiting substance and androgens (testosterone and dihydrotestosterone) during fetal development. Since development of the male reproductive tract is under sex hormone control, changes in the incidence of hypospadias and cryptorchidism could therefore be considered as likely markers of endocrine disturbance.

Data from two birth defects surveillance systems in the USA have shown that the prevalence of hypospadias at birth has increased between the 1970s and 1990s. Similarly, analysis of the secular trends in the prevalence of cryptorchidism also indicates an increase over time. In a prospective study carried out by the John Radcliffe Hospital Cryptorchidism Study Group, 7441 boys from Oxford were examined for cryptorchidism at birth and then again at three months of age during 1984 - 1988. The cryptorchidism rate at birth was found to have increased by 35.1 %, and at three months of age by 92.7% compared with the rates reported in an earlier study for the mid-1950s in 3612 male infants in London. While direct comparison between these two studies is hampered by different inclusion criteria, it would seem that the prevalence of cryptorchidism has increased in Great Britain.

Considerable variation in the incidence of hypospadias has been reported for different malformation surveillance systems. Analysis of the birth prevalence rates for hypospadias and cryptorchidism collected through the International Clearing House for Birth Defects Monitoring System has revealed a wide inter-country variation in rates of hypospadias and cryptorchidism around the world. A factor of 3 or more could be observed between the highest rates (in USA and Israel for hypospadias, USA and Canada for cryptorchidism) and the lowest rates (Finland, Japan, China and South America for hypospadias; South America for cryptorchidism). Differences in methodologies and other factors make the comparison difficult. The secular evolution within various registries suggests an increase in hypospadias rates during the seventies and the eighties in USA, Scandinavia and Japan. No change was observed in Canada, a country geographically very close to the USA. For both pathologies a tendency towards a decline of rates has been found after 1985.

A number of epidemiological studies have suggested that exposure to pesticides may be linked to male reproductive tract abnormalities in Granada, Spain, Norway, Colombia, and the United States. In Denmark, analysis of the data from all live male infants discharged from Danish hospitals with a diagnosis of cryptorchidism or hypospadias between 1983 and 1992 demonstrated a significantly increased risk of cryptorchidism but not hypospadias in sons of women working in gardening (OR 1.7, 95% CI 1.1-2.4).

In animal experiments, cryptorchidism has been induced with gestational exposure to suspected estrogenic and anti-androgenic chemicals, such as mono-n-butyl phthalate in rats and flutamide in pigs. Mid-gestational exposure to TCDD has produced cryptorchidism, reduced germ cell numbers and epididymal abnormalities in pigs, accompanied by reduced estrogen receptor-a mRNA expression in the gubernaculum and epididymis and increased estrogen receptor-a protein levels in the testis.

Animal studies demonstrate that exposure to estrogens during development can result in cryptorchidism and hyospadias. In humans, the induction of reproductive tract abnormalities (epididymal cysts, cryptorchdism and other genital abnormalities) in sons of DES-exposed mothers has been well documented. However, meta-analysis of 14 human studies on the influence of either oral contraceptives (less potent than DES) or progestagens has not produced any convincing evidence of an effect of prenatal exposure. The possible role of exogenous estrogens in the maternal diet in hypospadias has recently been investigated. Mothers who were vegetarian during pregnancy had an increased risk of giving birth to a boy with hypospadias compared with omnivores who did not supplement their diet with iron. (OR 4.99, 95% CI 2.10-11.88). Omnivores who supplemented their diet with iron in the first half of pregnancy also had a raised risk (OR 2.07, 95% CI 1.00-4.32). It was suggested that vegetarians would have a greater exposure to phytoestrogens than omnivores and this might explain the raised risk in that group.

Known risk factors associated with cryptorchidism include ethnicity, a family history of cryptorchidism, low birth weight, use of analgesics during pregnancy, birth order, maternal obesity, Caesarean delivery, pre-term birth and congenital malformations. Several of these are also risk factors for hypospadias. Evidence of a seasonal effect with peaks for cryptorchidism occurring at different times of the year in various studies has also been reported, although the significance of this finding has yet to be determined.

The data on secular trends in the incidence of hypospadias and cryptorchidism should be interpreted with considerable caution, given the lack of longitudinal studies and the consequent difficulties in comparing data from separate studies.


Useful Links
Des Moines University: Male Reproductive System Disease

Environmental Protection Agency (EPA): Developmental Origins of Male Reproductive Tract Disorders

Health Central: Male Reproductive System Disorder

Video Presentation: Disorders of the Male Reproductive System


Further Reading
Arbuckle TE, Hauser R, Swan SH, Mao CS, Longnecker MP, Main KM, Whyatt RM, Mendola P, Legrand M, Rovet J, Till C, Wade M, Jarrell J, Matthews S, Van Vliet G, Bornehag CG, Mieusset R. (2008) Meeting report: measuring endocrine-sensitive endpoints within the first years of life. Environmental Health Perspectives 116(7):948-951.

Chia SE. (2000) Endocrine disruptors and male reproductive function--a short review. International Journal of Andrology 23(Suppl 2):45-46.

Fisher JS. (2004) Environmental anti-androgens and male reproductive health: focus on phthalates and testicular dysgenesis syndrome. Reproduction 127(3):305-315.

Foster WG. (1998) Endocrine disruptors and development of the reproductive system in the fetus and children: is there cause for concern? Canadian Journal of Public Health 89(Suppl 1):S37-41.

Garry VF, Schreinemachers D, Harkins M, Griffith J. (1996) Pesticide appliers, biocides, and birth defects in rural Minnesota. Environmental Health Perspectives 104(4):394-399.

Garry VF, Harkins ME, Erickson LL, Long-Simpson LK, Holland SE, Burroughs BL. (2002) Birth defects, season of conception, and sex of children born to pesticide applicators living in the Red River Valley of Minnesota, USA. Environmental Health Perspectives 110(Suppl 3):441-449.

Grady R, Sathyanarayana S. (2012) An update on phthalates and male reproductive development and function. Current Urology Reports 13(4):307-310.

Guerrero-Bosagna CM, Skinner MK. (2009) Epigenetic transgenerational effects of endocrine disruptors on male reproduction. Seminars in Reproductive Medicine 27(5):403-408.

Hosie S, Loff S, Witt K, Niessen K, Waag KL. (2000) Is there a correlation between organochlorine compounds and undescended testes? European Journal of Pediatric Surgery 10(5):304-309.

Hughes IA, Martin H, Jääskeläinen J. (2006) Genetic mechanisms of fetal male undermasculinization: a background to the role of endocrine disruptors. Environmental Research 100(1):44-49.

Longnecker MP, Klebanoff MA, Brock JW, Zhou H, Gray KA, Needham LL, Wilcox AJ. (2002) Maternal serum level of 1,1-dichloro-2,2-bis (p-chlorophenyl) ethylene and risk of cryptorchidism, hypospadias, and polythelia among male offspring. American Journal of Epidemiology 155(4):313-322.

Mauduit C, Florin A, Amara S, Bozec A, Siddeek B, Cunha S, Meunier L, Selva J, Albert M, Vialard F, Bailly M, Benahmed M. (2006) Long-term effects of environmental endocrine disruptors on male fertility. Gynecologie, Obstetrique & Fertilite 34(10):978-984.

Mori C. (2001) Possible effects of endocrine disruptors on male reproductive function. Kaibogaku Zasshi Journal of Anatomy 76(4):361-368.

Pierik F., Burdof A., Deddens J., Juttmann R., Weber R. (2004) Maternal and Paternal Risk Factors for Cryptorchidism and Hypospadias: A Case-Control Study in Newborn Boys. Environmental Health Perspectives 112(15):1570-1576.

Safe S. (2002) Environmental estrogens: roles in male reproductive tract problems and in breast cancer. Reviews on Environmental Health 17(4):253-262.

Skakkebaek NE, Rajpert-De Meyts E, Main KM. (2001) Testicular dysgenesis syndrome: an increasingly common developmental disorder with environmental aspects. Human Reproduction 16(5):972-978.

Toledano M.B., Hansell A.L., Jarup L., Quinn M., Jick S., and Elliott P. (2003) Temporal trends in orchidopexy, Great Britain, 1992-1998. Environmental Health Perspectives 111(1):129-132.

Vrijheid M, Armstrong B, Dolk H, Van Tongeren M, Botting B. (2003) Risk of hypospadias in relation to maternal occupational exposure to potential endocrine disrupting chemicals. Occupational and Environmental Medicine 60(8):543-550, 2003.

Wiedner IS, Møller H, Jensen TK, Skakkebæk NE. (1998) Cryptorchidism and hypospadias in the sons of gardeners and farmers. Environmental Health Perspectives 106(12):793-796.


12. Precocious Puberty

Health Risk
Premature sexual development is linked to exposure to estrogenic contaminants. Precocious puberty has been reported in children exposed to environmental contaminants. Premature breast bud development was reported in young girls in Puerto Rico with exposure to phthalate esters. In Michigan premature puberty was recently reported in young girls with exposure to brominated diphenyl ethers.

The age of puberty onset has been suggested to be decreasing over at least two decades. However, the extent and persistence of the decline remains controversial. Moreover, there is no data available for regional differences in the sexual development. Too few studies have been conducted to permit an evaluation of the consistency of the data in this area. Animal studies have shown that exposure to environmental contaminants with estrogenic activity (chemicals that mimic some or all of the actions of estrogens) can accelerate the onset of puberty.

The biological trigger for the onset of puberty remains unknown. However, it is clear that estrogens accelerate the onset of sexual development. Hence, it is plausible that environmental estrogens can accelerate sexual development if present at sufficient concentration. It can be argued that if estrogenic contaminants can induce this effect then we should also be concerned about exposure to dietary phytoestrogens that are plant estrogens that although they have much shorter half-life than man-made chemicals are much more potent.

Overall the literature does not support the contention that environmental chemicals or dietary factors are having widespread effects on human sexual development. Nevertheless, accelerated sexual development is plausible in individuals exposed to high concentrations of estrogenic substances.


Useful Links
Canadian Women’s Health Network: Early puberty for girls. The new ‘normal’ and why we need to be concerned.

Mayo Clinic: Precocious Puberty

New York Times: Factors linked to a risk of early puberty

New York Times: Puberty Before Age 10: A New ‘Normal’?

Scientific America: As increasingly early puberty ups breast cancer risk, researchers search environment for clues.

University of Michigan: Precocious Puberty and Endocrine Disruptors


Further Reading
Colón I, Caro D, Bourdony CJ, Rosario O. (2000) Identification of phthalate esters in the serum of young Puerto Rican girls with premature breast development. Environmental Health Perspectives 108(9):895-900.

Den Hond E, Roels HA, Hoppenbrouwers K, Nawrot T, Thijs L, Vandermeulen C, Winneke G, Vanderschueren D, Staessen JA. (2002) Sexual maturation in relation to polychlorinated aromatic hydrocarbons: Sharpe and Skakkebaek's hypothesis revisited. Environmental Health Perspectives 110(8):771-776.

Diamanti-Kandarakis E, Gore AC. (Eds.) (2012) Endocrine Disruptors and Puberty. New York: Humana Press. ISBN 978-1-60761-561-3

Fisher MM, Eugster EA. (2013) What is in our environment that effects puberty? Reproductive Toxicology doi:10.1016/j.reprotox.2013.03.012.

Herman-Giddens ME, Slora EJ, Wasserman RC, Bourdony CJ, Bhapkar MV, Koch GG, Hasemeier CM. (1997) Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics 99(4):505-512.

Herman-Giddens ME, Steffes J, Harris D, Slora E, Hussey M, Dowshen SA, Wasserman R, Serwint JR, Smitherman L, Reiter EO. (2012) Secondary sexual characteristics in boys: data from the Pediatric Research in Office Settings Network. Pediatrics 130(5):1058-68.

Krstevska-Konstantinova M, Charlier C, Craen M, Du Caju M, Heinrichs C, de Beaufort C, Plomteux G, Bourguignon JP. (2001) Sexual precocity after immigration from developing countries to Belgium: evidence of previous exposure to organochlorine pesticides. Human Reproduction 16(5):1020-1026.

Meeker JD. (2012) Exposure to environmental endocrine disruptors and child development. Archives of Pediatrics & Adolescent Medicine 166(10):952-958.

Nah WH, Park MJ, Gye MC. (2011) Effects of early prepubertal exposure to bisphenol A on the onset of puberty, ovarian weights, and estrous cycle in female mice. Clinical and Experimental Reproductive Medicine 38(2):75-81.

Özen S, Darcan Ş (2011) Effects of environmental endocrine disruptors on pubertal development. Journal of Clinical Research in Pediatric Endocrinology 3(1):1-6.

Vasiliu O., Muttineni J., Karmaus W. (2004) In utero exposure to organochlorines and age at menarche. Human Reproduction 19(7):1506-1512.

Wu T, Buck GM, Mendola P. (2003) Blood lead levels and sexual maturation in U.S. girls: the Third National Health and Nutrition Examination Survey, 1988-1994. Environmental Health Perspectives 111(5):737-741.

Yum T, Lee S, Kim Y. (2013) Association between precocious puberty and some endocrine disruptors in human plasma. Journal of Environmental Science and Health A Toxic/Hazardous Substances & Environmental Engineering 48(8):912-917.


13. Thyroid Hormones

Health Risk
There is concern that brain development and cognitive function are impaired in the children of women exposed to a variety of persistent man-made pollutants during pregnancy. Therefore it has been suggested that environmental contaminant exposure can alter thyroid physiology and cause adverse health effects particularly in children. It has long been recognized that impairment of thyroid physiology during critical periods of fetal and neonatal development can cause permanent deficiencies in brain and sensory organ function. The severity and persistence of these deficits depends on the severity of maternal/fetal and/or postnatal hypothyroidism. Hypothyroidism is a condition in which the thyroid gland fails to produce enough thyroid hormone. Severe hypothyroidism may be caused by dietary iodine deficiency (iodine being essential for thyroid hormone production), the inability to synthesize thyroid hormones (genetic) and consumption of large quantities of substances known to impair thyroid hormone synthesis (i.e. goitrogens from canola seed meal, sorghum). There is also evidence to suggest that fetal alcohol syndrome may be a consequence of reduced brain sensitivity to the action of thyroid hormone. Table salt is now iodized to prevent iodine deficiency, and thus, impaired thyroid function. Newborns are now screened regularly for serum thyroid hormone to identify children with metabolic deficiencies. It has recently been demonstrated that even subtle reductions in maternal thyroid status are associated with reduced cognitive, motor and/or sensory ability in offspring.

Numerous in vivo studies in lab animals indicate that chemical contaminants, at sufficiently high doses, can reduce blood levels of the major circulating form of thyroid hormone (thyroxine or T4). Reduced circulating T4 levels have been demonstrated in rats exposed to ubiquitous persistent pollutants including but not limited to: dioxins, polychlorinated biphenyls - PCBs, hexachlorobenzene. Other studies have demonstrated that PCB, when administered to pregnant or lactating rats at concentrations comparable to dosages causing thyroid impairment, produced neurodevelopment deficits in the resulting pups. Similarly, developmental neurotoxicity of PCB has also been observed in monkeys exposed to PCB in utero. Neurodevelopmental effects are also induced in rats made severely hypothyroid by treatment with an antithyroid drug, propylthiouracil (PTU). These neurotoxic effects can be reversed in PTU-treated animals using the active form of thyroid hormone (triodothyronine or T3). This study suggests that it is possible that at least some of the effects of PCB on neurodevelopment may be mediated via the disruption of thyroid hormone homeostasis.

The association between persistent pollutant exposure and neurodevelopment in children has been examined in several large scale studies with estimates of maternal and fetal exposure and with detailed measures of the cognitive, sensory and motor functions of the resulting children. Results from these studies suggest that subtle neurodevelopmental delays were associated with fetal exposure to PCB. However, the effects of a variety of other potential neurotoxic substances (metals, dioxins and furans, etc.) that may have been associated with PCB exposure were not consistently examined. In the majority of these studies, no attempt was made to correlate either neurobehaviour or persistent pollutant exposure with measures of thyroid status, making speculation on the role of hormonal impairment difficult. It should be noted that PCB exposure levels associated with subtle developmental effects in humans are well below the exposure levels that led to neurodevelopmental impairment in either rats or monkeys. The few studies that have examined the association between persistent pollutant exposure during pregnancy and thyroid status have found that a slight reduction in circulating T4 and or an elevation in thyroid stimulating hormone (TSH - the pituitary signal for thyroid hormone synthesis and release) in children is correlated with umbilical cord or maternal serum concentrations of dioxin-like compounds (including some PCBs). All of the T4 and TSH levels seen in these studies were within the normal clinical range suggesting that the effects are subtle at best. It is not currently clear to what extent persistent chemicals may impair neurodevelopment and, what if any, are the effects on thyroid hormone homeostasis.

That disruption of thyroid physiology can impair brain and sensory organ development is beyond question. However, whether exposure to persistent contaminants can disrupt thyroid physiology in human children to the extent necessary to cause neurodevelopment effects is not known. Animal studies demonstrating that PCB, dioxin and other persistent pollutants can impair thyroid homeostasis in rodents may not translate to humans because of differences in serum T4 binding proteins. Rodent exposure to PCBs and other substances, leads to an increased metabolic clearance of thyroid hormone from the blood because of impaired binding of T4 to transthyretin, the major T4 carrier protein in rodents, and increased liver catabolic activity. In humans, the major serum T4 carrier protein, thyroid binding globulin, binds T4 more tightly than transthyretin, resulting in a much slower rate of T4 turnover than in rats. The more rapid turnover in rats means that rats are far more vulnerable to hypothyroidism as the thyroid gland has less capacity to keep replacing the T4 cleared. Activators of metabolic clearance are therefore less likely to impair human thyroid function than rats. However, deficiency of iodine or exposure to substances that impair thyroid hormone synthesis may increase vulnerability to the effects of persistent pollutants in causing hypothyroidism. In the absence of direct human evidence for a causal relationship between thyroid hormone levels, exposure to environmental chemicals and relevant alterations in physiological function, it is difficult to ascertain whether exposure to chemical agents has any biologically relevant effects on thyroid function in humans.

Evidence indicates that environmental agents in sufficient concentrations affect thyroid function in animals. However, the extremely low amounts of chemicals present in humans and the minimal evidence of biologically-relevant alterations in thyroid hormone levels in exposed subjects do not support the contention that persistent chemical exposure impairs thyroid homeostasis in humans.


Useful Links
British Thyroid Foundation: Your Thyroid Gland

Cambridge Scientific Abstracts (CSA): Thyroid Hormone Disorders

Canadian Centre for Occupational Health and Safety: Endocrine disruptors and endocrine system

Encyclopedia Britannica: Thyroid gland

EndocrineWeb: How Your Thyroid Works

Johns Hopkins University: What is thyroid hormone?

Science Daily: Thyroid Hormone

Thyroid Disease Manager

Thyroid Foundation of Canada: About Thyroid Disease

Tulane University: Thyroid


Andra SS, Makris KC. (2012) Thyroid disrupting chemicals in plastic additives and thyroid health. Journal of Environmental Science and Health C Environmental Carcinogenesis and Ecotoxicology Reviews 30(2):107-51.

Boas M, Feldt-Rasmussen U, Main KM. (2012) Thyroid effects of endocrine disrupting chemicals. Molecular and Cellular Endocrinology 355(2):240-248.

Gentilcore D, Porreca I, Rizzo F, Ganbaatar E, Carchia E, Mallardo M, De Felice M, Ambrosino C. (2013) Bisphenol A interferes with thyroid specific gene expression. Toxicology 304:21-31.

Jugan ML, Levi Y, Blondeau JP. (2010) Endocrine disruptors and thyroid hormone physiology.  Biochemical Pharmacology 79(7):939-947.

Li MH, Hsu PC, Guo YL. (2001) Hepatic enzyme induction and acute endocrine effects of 2,2',3,3',4,6-hexachlorobiphenyl and 2,2'3,4,5,6-hexachlorobiphenyl in prepubertal female rats. Archives of Environment Contamination Toxicology 41(3):381-385.

Longnecker MP, Gladen BC, Patterson DG, Rogan WJ. (2000) Polychlorinated biphenyl (PCB) exposure in relation to thyroid hormone levels in neonates. Epidemiology 11(3):249-254.

Maranghi F, De Angelis S, Tassinari R, Chiarotti F, Lorenzetti S, Moracci G, Marcoccia D, Gilardi E, Di Virgilio A, Eusepi A, Mantovani A, Olivieri A. (2013) Reproductive toxicity and thyroid effects in Sprague Dawley rats exposed to low doses of ethylenethiourea. Food and Chemical Toxicology doi:10.1016/j.fct.2013.05.048.

Mastorakos G, Karoutsou EI, Mizamtsidi M, Creatsas G. (2007) The menace of endocrine disruptors on thyroid hormone physiology and their impact on intrauterine development. Endocrine. 31(3):219-237.

Parham F, Wise A, Axelrad DA, Guyton KZ, Portier C, Zeise L, Thomas Zoeller R, Woodruff TJ. (2012) Adverse effects in risk assessment: modeling polychlorinated biphenyls and thyroid hormone disruption outcomes in animals and humans. Environmental Research 116:74-84.

Pelletier C, Doucet E, Imbeault P, Tremblay A. (2002) Associations between weight loss-induced changes in plasma organochlorine concentrations, serum T(3) concentration, and resting metabolic rate. Toxicological Sciences 67(1):46-51.

Wang T, Lu J, Xu M, Xu Y, Li M, Liu Y, Tian X, Chen Y, Dai M, Wang W, Lai S, Bi Y, Ning G. (2013) Urinary bisphenol a concentration and thyroid function in Chinese adults. Epidemiology 24(2):295-302.

Wise A, Parham F, Axelrad DA, Guyton KZ, Portier C, Zeise L, Zoeller RT, Woodruff TJ. (2012) Upstream adverse effects in risk assessment: a model of polychlorinated biphenyls, thyroid hormone disruption and neurological outcomes in humans. Environmental Research 117:90-99.


14. Immune System

Health Risk
Interaction between the immune and endocrine systems is well documented and therefore it has been suggested that the immune system may be susceptible to endocrine disruption. The immune system can be affected by the direct actions of chemicals on specific target components of this system characterized by immunosuppression, which can lead to decreased resistance to microbial agents or immunoenhancement, leading to allergy.

Generally, mortality from infectious diseases in industrialized countries has decreased in the last century. This can be attributed to improved sanitation, housing and nutrition and the introduction of effective immunizations and therapeutic agents. In the past twenty years, however, a small rise in the mortality rate from infectious diseases has occurred due to increased antibiotic resistance and the emergence of AIDS and other viral infections. The incidence of asthma, an immune disorder, has increased world-wide at the rate of about 50% per decade. Risk factors for asthma include exposure to indoor allergens (dust mites, cats, cockroaches), tobacco smoke, chemical irritants and genetics. It is suspected that the rise in asthma incidence is related to the increase in urbanization, but this requires further study. Asthma is associated with inflammation of the air passages in the lungs resulting in swelling and restriction of the airways. An underestimated risk factor for asthma is allergic rhinitis, another hypersensitivity disorder, characterized by allergen-induced inflammation of the membranes lining the nose.

Evidence regarding a cause-effect relationship between endocrine-disrupting chemicals and immune system dysfunction is controversial. Many studies have reported that accidental exposures to environmental toxicants (PCBs, PCDFs) have been associated with immune dysfunctions including respiratory ailments and skin lesions in both exposed individuals and in children exposed in utero. However, in many cases immune parameters reported for exposed individuals were within the normal range. In another example of accidental exposure, Vietnam veterans exposed to TCDD (Agent Orange) have reported health effects as a result of their exposure; however, immune parameters are not significantly different from unexposed men. Chronic occupational exposure to low levels of chemicals is not strongly associated with immune dysfunction. While there are some changes in the levels of immune system parameters, there is no evidence of increased incidence of disease. Lactational transfer of endocrine-disrupting chemicals to children has been shown to be associated with alterations in lymphocytes and immunoglobulins. There are several studies demonstrating an increased risk of developing otitis media with pre- and post-natal organochlorine exposure, while other studies failed to find an association. In general, epidemiological studies may report increased incidences of a particular health concern, however, changes in immune parameters (antibodies, lymphocytes) are often not observed.

It is well-established that environmental toxicants can affect immune system parameters; however, it is controversial whether these observed adverse effects are mediated by an endocrine-disrupting mechanism of action as opposed to direct toxicity. Children and adolescents exposed to PCBs and PCDFs in Taiwan through consumption of contaminated rice oil (YuCheng disease) exhibited decreased serum IgA, IgM, cytotoxic T cells and suppressor T cells with cell-mediated immune system dysfunction. Infants born to mothers exposed during pregnancy had increased incidence of respiratory infections and middle ear diseases. In a study of Inuit children, breast milk levels of organochlorines (p,p'-DDE, hexachlorobenzene, dieldrin) were correlated with increased incidence of ear disorder otitis media. Contamination of the arctic food chain by organochlorines has led to the bioaccumulation of contaminants in human populations inhabiting the arctic region. Contaminants, particularly lipophilic organochlorines, are transferred to nursing infants through breast-feeding. The incidence of non-Hodgkin lymphoma (NHL) has increased in many countries with risk factors for the disease including exposure to certain pesticides, organochlorines and Epstein-Barr virus. In a case-control study serum levels of PCBs, p,p'-DDE, chlordanes, hexachlorobenzene and other contaminants were measured in individuals with NHL (cases) and controls. Antibody titers to the Epstein-Barr antigen were correlated to an increased risk for NHL and were correlated to concentrations of organochlorines. High serum concentrations of the PCB-type chemicals and the chlordanes were associated with increased risk for NHL. The effects of environmental toxicants on the immune system have been widely studied using animal models. TCDD has been shown to induce premature terminal differentiation of thymocytes leading to changes in the thymic cortical epithelium resulting in atrophy of the thymus in rodents. TCDD suppresses cell-mediated immunity, delayed hypersensitivity and generation of cytotoxic T cells in a dose-dependent manner. In wildlife studies, birds exposed to organochlorines exhibit immunosuppression. However, the mechanisms for these effects are not known.

Many potential endocrine toxicants have been shown to be immunotoxic; however, it is controversial whether the effects on the immune system are mediated through disruption of the endocrine system or are the result of direct toxicity. In animal models and cell lines, chemicals such as TCDD, some PCBs, PCDD, PCDFs have been shown to bind to the aryl hydrocarbon receptor (AhR). Thus, by binding to the receptor, these organochlorine chemicals trigger AhR-mediated expression of genes involved in cell proliferation and differentiation causing myelosuppression, immunosuppression, thymic atrophy and inhibition of immune complement system components in many animal species. Timing of exposure is relevant as impairment to the immune system is more severe if exposure occurs during pre- or post-natal life compared to exposure in adult animals. Maturation of the immune system in rodents is especially vulnerable to adverse effects of dioxin-like compounds, chlordane, hexachlorobenzene, polycyclic aromatic hydrocarbons, DDT, and kepone. Similarly in humans, the immune system is vulnerable to chemical exposure during fetal and post-natal development.

Reproductive hormones have been shown to regulate the immune system. Pre-menopausal women tend to have higher immunoglobulin concentrations, stronger primary and secondary responses and increased resistance to the induction of immunological tolerance. The predominance of autoimmune diseases (Graves' disease, systemic lupus erythematosis, multiple sclerosis, rheumatoid arthritis) among women suggests that reproductive steroid hormones may modulate immunologic susceptibility. Estrogen has been shown to regulate the expression, distribution and activity of immune chemicals called cytokines. Studies using mouse lymphocytes have shown that estrogen enhances production of immune chemicals such as interleukins and interferons while androgens decreased the production of these chemicals. The immune system, through cytokine and interleukin-mediated pathways can regulate the reproductive system by inducing the release of gonadotropins LH and FSH.

There is insufficient evidence to demonstrate that exposure to toxicant-induced disruption of the immune system involves an endocrine mechanism. Many studies report increased incidence of adverse health effects following exposure, however, immune parameters, where measured, are often within the normal range. Animal studies provide some evidence that endocrine toxicants may impair the immune system, but additional studies are required. The regulation of the immune system by the endocrine system may render the immune system vulnerable to endocrine disruption. A greater understanding of both systems, along with sound epidemiological data are required to determine whether chemicals alter immune function via an endocrine disruption mechanism of action.


Useful Links
Diabetes and the Environment: Endocrine Disruption and Immune System

Emerging science on the impacts of endocrine disruptors on the immune system and disease resistance.

Marine Science Today: Endocrine Disruptors Lead to Lowered Immunity in Fish

United Nations Environment Programme (UNEP): State of the science of endocrine disrupting chemicals – 2012. Chapter 2.11 Endocrine disruptors and immune function, immune diseases, and disorders in humans and wildlife


Further Reading
Ahmed SA. (2000) The immune system as a potential target for environmental estrogens (endocrine disrupters): a new emerging field. Toxicology 150(1-3):191-206.

Baccarelli A, Mocarelli P, Patterson DG, Bonzini M, Pesatori A, Caporaso N, Landi MT. (2002)  Immunologic effects of dioxin: New results from Seveso and comparison with other studies. Environmental Health Perspectives 110(12):1169-1173.

Bennasroune A, Rojas L, Foucaud L, Goulaouic S, Laval-Gilly P, Fickova M, Couleau N, Durandet C, Henry S, Falla J. (2012) Effects of 4-nonylphenol and/or diisononylphthalate on THP-1 cells: impact of endocrine disruptors on human immune system parameters. International Journal of Immunopathology and Pharmacology 25(2):365-376.

Cantor KP, Strickland PT, Brock JW, Bush D, Helzlsouer K, Needham LL, Zahm SH, Comstock GW, Rothman N. (2003) Risk of non-Hodgkin's lymphoma and prediagnostic serum organochlorines: ss-hexachlorocyclohexane, chlordane/heptachlor-related compounds, dieldrin, and hexachlorobenzene. Environmental Health Perspectives 111(2):179-84.

Chalubinski M, Kowalski ML. (2006) Endocrine disrupters--potential modulators of the immune system and allergic response. Allergy 61(11):1326-1335.

Clayton EM, Todd M, Dowd JB, Aiello AE. (2012) The impact of bisphenol A and triclosan on immune parameters in the U.S. population, NHANES 2003-2006. Environmental Health Perspectives 119(3):390-396.

Dietert RR. (2012) Misregulated inflammation as an outcome of early-life exposure to endocrine-disrupting chemicals. Reviews on Environmental Health 27(2-3):117-131.

Inadera H. (2006) The immune system as a target for environmental chemicals: Xenoestrogens and other compounds. Toxicology Letters 164(3):191-206.

Kramer S, Hikel SM, Adams K, Hinds D, Moon K. (2012) Current status of the epidemiologic evidence linking polychlorinated biphenyls and non-hodgkin lymphoma, and the role of immune dysregulation. Environmental Health Perspectives 120(8):1067-1075.

Kuo CH, Yang SN, Kuo PL, Hung CH. (2012) Immunomodulatory effects of environmental endocrine disrupting chemicals. Kaohsiung Journal of Medical Sciences 28(7 Suppl):S37-42

Lee MH, Chung SW, Kang BY, Park J, Lee CH, Hwang SY, Kim TS. (2003) Enhanced interleukin-4 production in CD4+ T cells and elevated immunoglobulin E levels in antigen-primed mice by bisphenol A and nonylphenol, endocrine disruptors: involvement of nuclear factor-AT and Ca2+. Immunology 109(1):76-86.

Rogers JA, Metz L, Yong VW. (2013) Review: Endocrine disrupting chemicals and immune responses: a focus on bisphenol-A and its potential mechanisms. Molecular Immunology 53(4):421-430.

ten Tusscher GW, Steerenberg PA, van Loveren H, Vos JG, von dem Borne AE, Westra M, van der Slikke JW, Olie K, Pluim HJ, Koppe JG. (2003) Persistent hematologic and immunologic disturbances in 8-year-old Dutch children associated with perinatal dioxin exposure. Environmental Health Perspectives 111(12):1519-1523.

Weisglas-Kuperus N, Vreugdenhil HJ, Mulder PG. (2004) Immunological effects of environmental exposure to polychlorinated biphenyls and dioxins in Dutch school children. Toxicology Letters 149(1-3):281-285.

Yurino H, Ishikawa S, Sato T, Akadegawa K, Ito T, Ueha S, Inadera H, Matsushima K. (2004) Endocrine disruptors (environmental estrogens) enhance autoantibody production by B1 cells. Toxicological Sciences 81(1):139-147.



  • Karen Phillips
  • Warren Foster
  • Ricky Cheung
  • Nagarajkumar Yenugadhati
  • Morgan MacNeill
  • Nataliya Karyakina
  • James Gomes
  • Don Wigle

Last reviewed: July 10, 2013


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