Reproductive toxicity refers to the potential risk from a given chemical, physical or biologic agent to adversely affect both male and female fertility as well as offspring development. [1] Reproductive toxicants may adversely affect sexual function, ovarian failure, fertility as well as causing developmental toxicity in the offspring. [2] [3] Lowered effective fertility related to reproductive toxicity relates to both male and female effects alike and is reflected in decreased sperm counts, semen quality and ovarian failure.
Infertility is medically defined as a failure of a couple to conceive over the course of one year of unprotected intercourse. [4] Primary infertility indicates that a person has never been able to achieve pregnancy while secondary inferility is defined as a person having at least one pregnancy before. [5] As many as 20% of couples experience infertility. [4] Infertility may be caused by an issue along any part of the process of fertilizing an egg through birth of the child. This can include: the release of the egg, the ability of the sperm to fertilize the egg, the implantation of the egg in the uterine wall, and the ability of the fetus to complete development without miscarriage. [6] Among males oligospermia is defined as a paucity of viable spermatozoa in the semen, whereas azoospermia refers to the complete absence of viable spermatozoa in the semen. [4] Males may also experience issues in sperm motility and morphology, which means the sperm are less likely to make it to the egg or to be able to fertilize the egg. [6] Female infertility could be a result of an issue regarding their uterus, ovaries, or fallopian tubes and can be impacted by various diseases, endocrine/hormone disruption, or reproductive toxicant. [6] [5]
The Globally Harmonized System of Classification and Labelling of Chemicals (GHS) separates reproductive toxicity from germ cell mutagenicity and carcinogenicity, even though both these hazards may also affect fertility. [7]
Many drugs can affect the human reproductive system. Their effects can be
However, most studies of reproductive toxicity have focused on occupational or environmental exposure to chemicals and their effects on reproduction. Both consumption of alcohol and tobacco smoking are known to be "toxic for reproduction" in the sense used here.
One well-known group of substances which are toxic for reproduction are teratogens – substances which cause birth defects. (S)-thalidomide is possibly the most notorious of these. [8]
Another group of substances which have received much attention (and prompted some controversy) as possibly toxic for reproduction are the so-called endocrine disruptors. [8] Endocrine disruptors change how hormones are produced and how they interact with their receptors. [9] Endocrine disruptors are classified as estrogenic, anti-estrogenic, androgenic or anti-androgenic. Each category includes pharmaceutical compounds and environmental compounds. Estrogenic or androgenic compounds will cause the same hormonal responses as the sex steroids (estrogen and testosterone). However anti-estrogenic and anti-andogenic compounds bind to a receptor and block the hormones from binding to their receptors, thus preventing their function. A few examples of the many types of endocrine disruptors are trenbolone (androgenic), flutamide (anti-androgenic), diethylstilbestrol (estrogenic), bisphenol A (estrogenic) and tributyltin (anti-estrogenic). [10] [11]
However, many substances which are toxic for reproduction do not fall into any of these groups: lead compounds, for example, are considered to be toxic for reproduction [10] [11] given their adverse effects on the normal intellectual and psychomotor development of human babies and children.
Lead, a heavy metal that can exist in both organic and inorganic forms, and is associated with adverse effects on male libido, erectile disfunction, premature ejaculation and poor sperm quality. [12] Lead is also associated with negative effects on the female reproductive system particularly for pregnant people. [13] Elevated blood lead levels can increase risk of preeclampsia and miscarriage and can lead to birth defects. [14] [15] Lead is believed to predominantly affect male reproduction by the disruption of hormones, which reduces the quantity of sperm production in the seminiferous tubules. It has also been proposed that lead causes poor semen quality by promoting the generation of reactive oxygen species such as hydrogen peroxide due to lipid peroxidation, which can cause cellular damage. [16] [17] Lead can be found in contaminated soil, water, as well as manufactured goods like jewelry, toys, and paint. [18] Common routes of exposure are inhalation and digestion, though dermal exposure can occur albeit less frequently. [18] Occupational exposures remain a high risk, particularly for industries such as battery/electronic recycling, construction, mining, smelting, and welders or any other industry which interacts with lead. [13] Families and cohabitants of the above workers may be at risk of take-home exposure and may need to take precautions to avoid reproductive impacts. [19]
Cadmium is a heavy metal used in jewelry making, electronics, welding and galvanizing steel. [20] The human route of exposure is primarily inhalational or oral; environmental exposure among the non-occupationally exposed can occur due to exposure to cigarette smoking. [20] The oral route of exposure can occur due to ingesting plants and shellfish that have taken up cadmium from water and soil. [20] Exposure to cadmium results in adverse male fertility in terms of decreased spermatogenesis, semen quality, sperm motility and impaired hormonal synthesis. [21] Likewise, exposure to cadmium impairs female fertility in terms of menstrual cycle regularity and reproductive hormonal balance. [21] Cadmium exposure can negatively impact fetal development throughout the gestation as well as ovulation and implantation. [22]
Hexavalent chromium ( Cr VI) is used in the electronics industry and for metal plating. [23] Chromium exposure is primarily inhalation or through ingestion. [24] Human and animal studies show that exposure to hexavalent chromium decreases semen quality and sperm counts. [25]
Elemental mercury( Hg0) is a metal that exists as liquid form at room temperature and is commonly found in thermometers, blood pressure cuffs and dental amalgams. In terms of exposure, the route of absorption is primarily via inhalation through mercury vapor, which can in turn lead to mercury poisoning. [26] Occupational exposure to inorganic mercury can occur in industries such as dentistry, fluorescent lamp production, and Chloralkali workers. [27] Data among female dental technicians exposed to mercury vapors have demonstrated decreased fertility among those who were exposed and practiced poor industrial hygiene while handling dental amalgams. [26] [28] Elemental and organic mercury can cross the blood brain barrier, like many other heavy metals, making it particularly significant for pregnant people as it can impact fetal development and birth outcomes. [27] Among female workers in mercury smelting plants an increase in spontaneous abortions has been reported. [28]
Dibromochloropropane (DBCP) is used as a pesticide against nematodes in the agricultural industry. [29] DBCP is one of the most well-known reproductive toxicants known to cause testicular toxicity. [12] Workers in chemical factories exposed to dibromochloropropane have been shown to develop dose-dependent oligospermia and azoospermia. [12] Additional studies also demonstrated that DBCP-exposed workers in banana and pineapple plantations in central America and other countries also developed oligospermia and azoospermia. [30] In 1977, the United States Environmental Protection Agency banned the use of DBCP in agriculture due to its effect on male fertility. [31] Despite being banned from use in agriculture, DBCP is still used as an intermediate in chemical manufacturing as well as a reagent in research. [31]
Ethylene dibromide
Ethylene dibromide (EDB) is a fumigant that was originally used to protect citrus fruits, grains and vegetables from insects. [32] Use of EDB in the United States was banned by the United States Environmental Protection Agency in 1984, however EDB is still used in the United States as fumigant to treat timber logs for beetles and termites. [32] Likewise, it is still used as an intermediate in chemical manufacturing. [32] Exposure to EDB has been shown to adversely affect male fertility by leading to a decreased sperm counts, decreased numbers of viable sperm and increased abnormal sperm morphology. [33] [34] The primary route of exposure is through inhalation. [32]
Solvent exposure is common among men and women working in industrial settings. Specific solvents including xylene, perchloroethylene, toluene and methylene chloride have been shown to be associated with a concurrent elevation in risk for spontaneous abortion [35]
Ionizing radiation in the form alpha, beta and gamma emissions are well known to adversely affect male and female fertility, as well as fetal development. [36] [37] Exposure to low doses of ionizing radiation can occur naturally in the environment or due to medical treatment or diagnosis, however, higher exposures may be associated with occupation. [36] Occupations with documented risk include: healthcare workers who interact with radioactive material, certain manufacturing processes, and airline personnel. [36] Exposure in the range of 0.1 to1.2 Gy is associated with spermatogonial injury; whereas between 4-6 Gy reductions of sperm counts have been reported. [37] Ionizing radiation is considered a hazard particularly in pregnancy, due to its potential impact of gestational development. [36] More specifically, ionizing radiation is associated with an increased risk of miscarriage and stillbirth. [38] Recent studies suggest that routine medical examinations that expose a pregnant person to ionizing radiation are not associated with an increase of risk of miscarriage or stillbirth. [39]
Radio frequency electromagnetic fields, such as those generated from mobile phone devices, have been shown to decrease semen quality production in experimental animal models; however human data is still equivocal at best. [40] [41] The International Association for the Research of Cancer(IARC) classifies radio frequency electromagnetic fields as a group 2B or possibly carcinogenic. [42]
Lipid soluble compounds that can cross the cell lipid bilayer and bind cytoplasmic steroid hormone receptors can translocate to the nucleus and act as estrogen agonists. [43] Diethylstilbestrol (DES), a synthetic estrogen, is one such endocrine disruptor and acts as an estrogen agonist. Diethylstilbestrol was used from 1938 to 1971 to prevent spontaneous abortions. [43] Diethylstilbestrol causes cancer and mutations by producing highly reactive metabolites, also causing DNA adducts to form. Exposure to diethylstilbestrol in the womb can cause atypical reproductive tract formation. Specifically, females exposed to diethylstilbestrol in utero during the first trimester have are more likely to develop clear cell vaginal carcinoma, and males have an increased risk of hypospadias. [44]
Bisphenol A (BPA) is used in polycarbonate plastic consumer goods and aluminum can liners. [45] BPA is an example of an endocrine disruptor which negatively affects reproductive development by acting as an estrogen mimicker (xenoestrogen) and a likely androgen mimicker. [46] Bisphenol A exposure in fetal female rats leads to mammary gland morphogenesis, increased formation of ovarian tumors, and increased risk of developing mammary gland neoplasia in adult life. In lab animal models, BPA is considered to be both an ovarian and uterine toxicant as it impairs endometrial proliferation, decreases uterine receptivity and decreases the chances for successful implantation of the embryo [47] The adverse reproductive toxicological impacts of bisphenol A have been better studied in females than in males. [48] [49] [47]
Antineoplastic drugs, commonly known as chemotherapy drugs, are considered hazardous drugs by the CDC, including hazardous to reproductive health. [50] Exposure to chemotherapy drugs most often occurs through treatment for cancer, however, unintentional occupational exposure may occur in for workers involved in pharmaceutical production, pharmacists or technicians preparing the drugs, and nurses or other healthcare professionals who are administering medication to patients. [51] Other hospital staff, particularly custodial workers, who interact or handle antineoplastic drugs in any capacity may also be at risk of exposure. [51] Exposure can occur through inhalation, skin contact, ingestion, or injection. [51]
Work schedule can become a reproductive toxicant when working hours are during the employee's typical sleeping hours (night shift), when a worker has an irregular work schedule (shift work) or long working hours. [52] Work schedule's reproductive toxicity is primarily a result of impact on regularity, quality, and rhythm of sleep. [52] Shift work is associated with menstrual disorders, which can in turn impact fertility. [52] [53] Irregular work schedule, working long hours, and working the night shift is associated with an increased risk of miscarriage and pre-term birth. [52] Many occupations engage in shift work, including requiring rotating work schedules, long hours, or night shift work. Some occupations that frequently engage in shift work include first responders, airline personnel, healthcare workers, and service workers. [52] The CDC estimates that fifteen-million Americans engage in shift work and 30% get less than six-hours of sleep. [52]
Physical demands can include bending, lifting, and standing. Physical demands are considered a reproductive toxicant as they can increase the risk of adverse outcomes during pregnancy. [54] Bending, lifting, and standing are often associated with occupational responsibilities as the risk is minimal unless physical activity is prolonged. [54] Standing and walking for more than three hours a day is associated with an increased risk of pre-term birth, while standing for six to eight hours a day is associated with an increased risk of miscarriage. [55] [56] The weight and frequency of lifting is also associated with increased risk of miscarriage and preterm birth, with estimates of loads over 10 kg, or frequency a cumulative 100 kg/day. [56] [57]
Noise is considered a reproductive toxicant due to its potential impact on fetal development during pregnancy. While pregnant people may be able to use proper hearing protection to conserve their own hearing, after the 20th week of development babies' ears are susceptible to hearing loss. [58] Pregnant people who are past 20 weeks of development should consider avoiding noises above 85 decibels, including at work and recreational activities. [58]
Phthalates, or phthalate esters, are esters of phthalic acid. They are mainly used as plasticizers, i.e., substances added to plastics to increase their flexibility, transparency, durability, and longevity. They are used primarily to soften polyvinyl chloride (PVC). Note that while phthalates are usually plasticizers, not all plasticizers are phthalates. The two terms are specific and unique and cannot be used interchangeably.
Endocrine disruptors, sometimes also referred to as hormonally active agents, endocrine disrupting chemicals, or endocrine disrupting compounds are chemicals that can interfere with endocrine systems. These disruptions can cause numerous adverse human health outcomes, including alterations in sperm quality and fertility; abnormalities in sex organs‚ endometriosis‚ early puberty‚ altered nervous system or immune function; certain cancers; respiratory problems; metabolic issues; diabetes, obesity, or cardiovascular problems; growth, neurological and learning disabilities, and more. Found in many household and industrial products, endocrine disruptors "interfere with the synthesis, secretion, transport, binding, action, or elimination of natural hormones in the body that are responsible for development, behavior, fertility, and maintenance of homeostasis ."
Dieldrin is an organochlorine compound originally produced in 1948 by J. Hyman & Co, Denver, as an insecticide. Dieldrin is closely related to aldrin, which reacts further to form dieldrin. Aldrin is not toxic to insects; it is oxidized in the insect to form dieldrin which is the active compound. Both dieldrin and aldrin are named after the Diels-Alder reaction which is used to form aldrin from a mixture of norbornadiene and hexachlorocyclopentadiene.
Environmental toxicants and fetal development is the impact of different toxic substances from the environment on the development of the fetus. This article deals with potential adverse effects of environmental toxicants on the prenatal development of both the embryo or fetus, as well as pregnancy complications. The human embryo or fetus is relatively susceptible to impact from adverse conditions within the mother's environment. Substandard fetal conditions often cause various degrees of developmental delays, both physical and mental, for the growing baby. Although some variables do occur as a result of genetic conditions pertaining to the father, a great many are directly brought about from environmental toxins that the mother is exposed to.
Anogenital distance (AGD) is the distance from the midpoint of the anus to the genitalia, the underside of the vagina, the clitoris or the scrotum. It is considered medically significant for a number of reasons, in both humans and other animals, including sex determination and as a marker of endocrine disruptor exposure. It is regulated by dihydrotestosterone, which can be disrupted by phthalates common in plastics.
Xenoestrogens are a type of xenohormone that imitates estrogen. They can be either synthetic or natural chemical compounds. Synthetic xenoestrogens include some widely used industrial compounds, such as PCBs, BPA, and phthalates, which have estrogenic effects on a living organism even though they differ chemically from the estrogenic substances produced internally by the endocrine system of any organism. Natural xenoestrogens include phytoestrogens which are plant-derived xenoestrogens. Because the primary route of exposure to these compounds is by consumption of phytoestrogenic plants, they are sometimes called "dietary estrogens". Mycoestrogens, estrogenic substances from fungi, are another type of xenoestrogen that are also considered mycotoxins.
Benzyl butyl phthalate (BBP) is an organic compound historically used a plasticizer, but which has now been largely phased out due to health concerns. It is a phthalate ester of containing benzyl alcohol, and n-butanol tail groups. Like most phthalates, BBP is non-volatile and remains liquid over a wide range of temperatures. It was mostly used as a plasticizer for PVC, but was also a common plasticizer for PVCA and PVB.
Male infertility refers to a sexually mature male's inability to impregnate a fertile female. In humans, it accounts for 40–50% of infertility. It affects approximately 7% of all men. Male infertility is commonly due to deficiencies in the semen, and semen quality is used as a surrogate measure of male fecundity. More recently, advance sperm analyses that examine intracellular sperm components are being developed.
Methoxychlor is a synthetic organochloride insecticide, now obsolete. Tradenames for methoxychlor include Chemform, Maralate, Methoxo, Methoxcide, Metox, and Moxie.
Environmental toxicology is a multidisciplinary field of science concerned with the study of the harmful effects of various chemical, biological and physical agents on living organisms. Ecotoxicology is a subdiscipline of environmental toxicology concerned with studying the harmful effects of toxicants at the population and ecosystem levels.
Bisphenol S (BPS) is an organic compound with the formula (HOC6H4)2SO2. It has two phenol functional groups on either side of a sulfonyl group. It is commonly used in curing fast-drying epoxy resin adhesives. It is classified as a bisphenol, and a close molecular analog of bisphenol A (BPA). BPS differentiates from BPA by possessing a sulfone group (SO2) as the central linker of the molecule instead of a dimethylmethylene group (C 2), which is the case of bisphenol A.
Health effects of pesticides may be acute or delayed in those who are exposed. Acute effects can include pesticide poisoning, which may be a medical emergency. Strong evidence exists for other, long-term negative health outcomes from pesticide exposure including birth defects, fetal death, neurodevelopmental disorder, cancer, and neurologic illness including Parkinson's disease. Toxicity of pesticides depend on the type of chemical, route of exposure, dosage, and timing of exposure.
Xenohormones or environmental hormones are compounds produced outside of the human body which exhibit endocrine hormone-like properties. They may be either of natural origin, such as phytoestrogens, which are derived from plants, or of synthetic origin. These compounds can cause endocrine disruption by multiple mechanisms including acting directly on hormone receptors, affecting the levels of natural hormones in the body, and by altering the expression of hormone receptors. The most commonly occurring xenohormones are xenoestrogens, which mimic the effects of estrogen. Other xenohormones include xenoandrogens and xenoprogesterones. Xenohormones are used for a variety of purposes including contraceptive & hormonal therapies, and agriculture. However, exposure to certain xenohormones early in childhood development can lead to a host of developmental issues including infertility, thyroid complications, and early onset of puberty. Exposure to others later in life has been linked to increased risks of testicular, prostate, ovarian, and uterine cancers.
Developmental toxicity is any developmental malformation that is caused by the toxicity of a chemical or pathogen. It is the structural or functional alteration, reversible or irreversible, which interferes with homeostasis, normal growth, differentiation, development or behavior. Developmental toxicity is caused by environmental insult, which includes drugs, alcohol, diet, toxic chemicals, and physical factors.
Toxicodynamics, termed pharmacodynamics in pharmacology, describes the dynamic interactions of a toxicant with a biological target and its biological effects. A biological target, also known as the site of action, can be binding proteins, ion channels, DNA, or a variety of other receptors. When a toxicant enters an organism, it can interact with these receptors and produce structural or functional alterations. The mechanism of action of the toxicant, as determined by a toxicant’s chemical properties, will determine what receptors are targeted and the overall toxic effect at the cellular level and organismal level.
A nonsteroidal estrogen is an estrogen with a nonsteroidal chemical structure. The most well-known example is the stilbestrol estrogen diethylstilbestrol (DES). Although nonsteroidal estrogens formerly had an important place in medicine, they have gradually fallen out of favor following the discovery of toxicities associated with high-dose DES starting in the early 1970s, and are now almost never used. On the other hand, virtually all selective estrogen receptor modulators (SERMs) are nonsteroidal, with triphenylethylenes like tamoxifen and clomifene having been derived from DES, and these drugs remain widely used in medicine for the treatment of breast cancer among other indications. In addition to pharmaceutical drugs, many xenoestrogens, including phytoestrogens, mycoestrogens, and synthetic endocrine disruptors like bisphenol A, are nonsteroidal substances with estrogenic activity.
Occupational toxicology is the application of toxicology to chemical hazards in the workplace. It focuses on substances and conditions that people may be exposed to in workplaces, including inhalation and dermal exposures, which are most prevalent when discussing occupational toxicology. These environmental and individual exposures can impact health, and there is a focus on identifying early adverse affects that are more subtle than those presented in clinical medicine.
Testicular dysgenesis syndrome is a male reproduction-related condition characterized by the presence of symptoms and disorders such as hypospadias, cryptorchidism, poor semen quality, and testicular cancer. The concept was first introduced by N.E. Skakkebæk in a research paper along with the department of Growth and Reproduction in Copenhagen University. The paper suggests the origin and underlying cause of TDS can be detected as early as in fetal life, where environmental and genomic factors could affect the development of the male reproductive system.
Antiandrogens in the environment have become a topic of concern. Many industrial chemicals, including phthalates and pesticides, exhibit antiandrogen activity in animal experiments. Certain plant species have also been found to produce antiandrogens. In animal studies, environmental antiandrogens can harm reproductive organ development in fetuses exposed in utero as well as their offspring.
Bisphenol A controversy centers on concerns and debates about the biomedical significance of bisphenol A (BPA), which is a precursor to polymers that are used in some consumer products, including some food containers. The concerns began with the hypothesis that BPA is an endocrine disruptor, i.e. it mimics endocrine hormones and thus has the unintended and possibly far-reaching effects on people in physical contact with the chemical.
Annex I, section 3.7 labelling and packaging of substances and mixtures, amending and repealing Directives 67/548/EEC and 1999/45/EC, and amending Regulation (EC) No 1907/2006.