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. Reproductive toxicants may adversely affect sexual function, ovarian failure, fertility as well as causing developmental toxicity in the offspring. 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 Infertility is medically defined as a failure of a couple to conceive over the course of one year of unprotected intercourse. Primary infertility indicates that a person has never been able to achieve pregnancy while secondary infertility is defined as a person having at least one pregnancy before. As many as 20% of couples experience infertility. 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. 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. 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. Female infertility could be a result of an issue regarding their uterus, ovaries, or fallopian tubes and can be affected by various diseases, endocrine/hormone disruption, or reproductive toxicant.
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.
Effects Many drugs can affect the human reproductive system. Their effects can be
desired (hormonal contraception), a minor unwanted side effect (many antidepressants) or a major public health problem (thalidomide).
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.
Another group of substances which have received much attention (and prompted some controversy) as possibly toxic for reproduction are the so-called endocrine disruptors. Endocrine disruptors change how hormones are produced and how they interact with their receptors. 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).Commission Directive 2004/73/EC of 29 August 2004 adapting to technical progress for the 29th time Council Directive 67/548/EEC on the approximation of the laws, regulations and administrative provisions relating to the classification, packaging and labelling of dangerous substances. OJEC L152, 30.04.2004, pp. 1–311 (index no. 082-001-00-6).Regulation (EC) No 1272/2008 of the European Parliament and of the Council of 16 December 2008 on classification, 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. OJEC L353, 31.12.2008, pp. 1–1355 at p. 444 (index no. 082-001-00-6).
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 given their adverse effects on the normal intellectual and psychomotor development of human babies and children.
Examples
Heavy metals
Lead
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. Lead is also associated with negative effects on the female reproductive system particularly for pregnant women. Elevated blood lead levels can increase risk of preeclampsia and miscarriage and can lead to birth defects. 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. Lead can be found in contaminated soil, water, as well as manufactured goods like jewelry, toys, and paint. Common routes of exposure are inhalation and digestion, though dermal exposure can occur albeit less frequently. 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. Families and cohabitants of the above workers may be at risk of take-home exposure and may need to take precautions to avoid reproductive effects.
Cadmium
Cadmium is a heavy metal used in jewelry making, electronics, welding and galvanizing steel. 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. The oral route of exposure can occur due to ingesting plants and shellfish that have taken up cadmium from water and soil. Exposure to cadmium results in adverse male fertility in terms of decreased spermatogenesis, semen quality, sperm motility and impaired hormonal synthesis. Likewise, exposure to cadmium impairs female fertility in terms of menstrual cycle regularity and reproductive hormonal balance. Cadmium exposure can negatively affect fetal development throughout the gestation as well as ovulation and implantation.
Chromium
Hexavalent chromium ( Cr VI) is used in the electronics industry and for metal plating. Chromium exposure is primarily inhalation or through ingestion. Human and animal studies show that exposure to hexavalent chromium decreases semen quality and sperm counts.
Mercury
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. Occupational exposure to inorganic mercury can occur in industries such as dentistry, fluorescent lamp production, and Chloralkali workers. 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. Elemental and organic mercury can cross the blood brain barrier, like many other heavy metals, making it particularly significant for pregnant women as it can affect fetal development and birth outcomes. Among female workers in mercury smelting plants an increase in spontaneous abortions has been reported.
Dibromochloropropane Dibromochloropropane (DBCP) is used as a pesticide against nematodes in the agricultural industry. DBCP is one of the most well-known reproductive toxicants known to cause testicular toxicity. Workers in chemical factories exposed to dibromochloropropane have been shown to develop dose-dependent oligospermia and azoospermia. Additional studies also demonstrated that DBCP-exposed workers in banana and pineapple plantations in Central America and other countries also developed oligospermia and azoospermia. In 1977, the United States Environmental Protection Agency banned the use of DBCP in agriculture due to its effect on male fertility. Despite being banned from use in agriculture, DBCP is still used as an intermediate in chemical manufacturing as well as a reagent in research.
Ethylene dibromide
Ethylene dibromide (EDB) is a fumigant that was originally used to protect citrus fruits, grains and vegetables from insects. 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. Likewise, it is still used as an intermediate in chemical manufacturing. 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. The primary route of exposure is through inhalation.
Industrial solvents
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
Ionizing radiation
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. 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. Occupations with documented risk include: healthcare workers who interact with radioactive material, certain manufacturing processes, and airline personnel. 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. Ionizing radiation is considered a hazard particularly in pregnancy, due to its potential effect of gestational development. More specifically, ionizing radiation is associated with an increased risk of miscarriage and stillbirth. 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.
Radio frequency electromagnetic fields
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. The International Association for the Research of Cancer(IARC) classifies radio frequency electromagnetic fields as a group 2B or possibly carcinogenic.
Endocrine disrupting compounds